Benzodiazepine receptor ligands III. Synthesis and biological evaluation of 2- and/or 3-substituted pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides

www.elsevier.nl/locate/farmac

Il Farmaco 54 (1999) 375–389

Benzodiazepine receptor ligands

III. Synthesis and biological evaluation of 2- and/or 3-substituted

pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides

G. Guerrini ^a, A. Costanzo ^a,*, F. Bruni ^a, G. Ciciani ^a, S. Selleri ^a, P. Gratteri ^a,

B. Costa ^b, C. Martini ^b, A. Lucacchini ^b

^aDipartimento di Scienze Farmaceutiche, Uni6ersita` degli Studi di Firenze, Via Gino Capponi 9, 50121 Florence, Italy

^bIstituto Policattedra Discipline Biologiche, Uni6ersita` degli Studi di Pisa, Via Bonanno 6, 56100 Pisa, Italy

Received 2 September 1998; accepted 30 March 1999

Abstract

A new series of 2- and/or 3-substituted pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides and their 8-chloro derivatives were

synthesized, and their benzodiazepine receptor (BZR) afﬁnities were evaluated in vitro in comparison to lead compound

3-ethoxycarbonyl-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (29) [1,2]. None of the new compounds showed signiﬁcant

afﬁnity for BZR. On the basis of a pharmacophore/receptor model suggested for lead compound 29, some hypotheses to explain

Keywords: 2- and/or 3-substituted pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide; Benzodiazepine receptor; Receptor binding

Recently, we reported the synthesis and evaluation of

the BZR afﬁnity of a series of pyrazolo[5,1-c][1,2,4]-

1. Introduction

benzotriazines and corresponding 5-oxides 3-, 7- and

In our studies on tricyclic heterocycles containing a

8-substituted with a variety of groups different for

pyrazole moiety with potential CNS activity, we fo-

lipophilic and electronic features and amounts of steric

cused on central benzodiazepine receptor (BZR) ligands

hindrance [2]. From binding data we found that the

[1,2]. In addition to the classic 1,4-benzodiazepines

best ligand was the 3-ethoxycarbonyl-8-chloropyra-

(1,4-BZs), a large number of ligands belonging to dif-

ferent chemical families have been shown to bind with

high afﬁnity to the GABA_A–BZR. BZ ligands act as

allosteric modulators of the GABA_A/chloride channel

zolo[5,1-c][1,2,4]benzotriazine 5-oxide (K_i35 nM), even

if compounds bearing at the 3-position bromine and at

the 8-position also a chlorine or a small lipophilic

group such as ethoxy- or methyl group showed good

supramolecular complex and have been classiﬁed as

afﬁnity. The pharmacological proﬁle of these new lig-

agonists, inverse agonists and antagonists if they en-

ands, evaluated by GABA-ratio (GR), was from ago-

hance, reduce or have no inﬂuence on the GABA_A-

gated chloride current.

nists for 3-ethoxycarbonyl derivatives (GR 1.61–2.67)

to partial agonists for 3-bromine derivatives (GR 1.14–

1.31) [2].

Agonists exhibit anxiolytic, anticonvulsant, muscle

relaxant and sedative/hypnotic activity, the inverse ago-

nists cause the opposite behavioral effects, such as

anxiogenesis and proconvulsant action, the antagonists

inhibit the action of both agonists and inverse agonists.

As part of a wider program of SAR studies, in order

to explain the BZR binding of the new pyrazolo[5,1-c]-

[1,2,4]benzotriazine ligands, it is very interesting to

focus the role of the substituent at 2- and/or 3-position

on receptor afﬁnity and on intrinsic activity in the

presence of a favorable substituent at the 8-position.

The importance of the rotable aromatic rings in

BZ-ligands to recognize and activate BZR and the rela-

* Corresponding author. Tel.: +39-55-2757296; fax: +39-55-

240776.

E-mail address: costanzo@farmﬁ.scifarm.uniﬁ.it (A. Costanzo)

PII: S0014-827X(99)00044-0

376

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

2. Chemistry

tionship between the full agonism spectrum activity and

the presence on the ligands of aromatic rings interact-

ing at lipophilic pocket L₃, have recently been outlined

[3–5].

The new compounds described here, are listed in

Tables 1 and 2.

In order to synthesize the 2- or 3-substituted pyra-

zolo[5,1-c][1,2,4]benzotriazine 5-oxides, the suitable 5-

aminopyrazoles were obtained following two different

synthetic methods (see Schemes 1 and 2). The aminopy-

razoles 1–6, 8–28 and the iminopyrazole 7, were cy-

clized to the triazine system (1a–28a) in 10% sodium

hydroxide following a known procedure [1,2].

2-Phenyl-3-cyanopyrazolo[5,1-c][1,2,4]benzotriazine

5-oxide (1a), 2-phenyl-3-cyano-8-chloropyrazolo[5,1-c]-

[1,2,4]benzotriazine 5-oxide (2a), and 2-methyl-3-cyano-

8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (9a),

after a normal work up to obtain the corresponding

amides (1b, 2b and 9b) and acids (1c, 2c and 9c), were

In this paper, the synthesis and evaluation of BZR

afﬁnity of

a new series of pyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxides and their 8-chloro derivatives

substituted at the 2- and the 3-positions with aromatic

or heteroaromatic groups with different lipophilic,

steric, and electronic features, are reported. These aro-

matic rings might change the afﬁnity and intrinsic

activity of this class of BZR ligands.

In addition to the 2-aromatic and 2-heteroaromatic

derivatives, the 2-methyl- and 2-ethoxycarbonyl-5-oxide

derivatives were also synthesized to verify if the 2-posi-

tion of pyrazole, not previously investigated by us,

tolerates any kinds of substituents.

Table 1

Chemical data for 5-aminopyrazoles

a

Comp.

R

R%

R%%

Formula (MW)

M.p.(°C) (recrystallization solvent) yield

1

2

3

4

5

6

Ph

CN

H

H,H

Ph

CN

H

Ph

2-FPh

3-FPh

4-FPh

2-ClPh

3-ClPh

4-ClPh

3,4-diClPh

2-Py

H

C₁₆H₁₁N₅O₂(305.31)

C₁₆H₁₁N₅O₂Cl (339.75)

C₁₅H₁₁N₄O₂Cl (314.74)

174–174 (i-propanol) 30%

234–235 (ethanol) 35%

180–182 (ethanol/water) 68%

153–155 (ethanol/water) 38%

200–201 (ethanol) 50%

213–214 (ethanol) 70%

211–212 (ethanol) 30%

192–193 (ethanol) 58%

186–187 (ethanol/water) 50%

157–158 (water) 45%

153–154 (lit. 153–155) (ethanol) 64%

168–169 (ethanol/water) 50%

133–134 (ethanol/water) 60%

129–130 (ethanol/water) 69%

166–167 (ethanol/water) 72%

174–175 (ethanol/water) 70%

141–142 (ethanol/water) 80%

128–129 (ethanol/water) 72%

132–133 (ethanol/water) 79%

129–130 (ethanol/water) 80%

155–156 (ethanol/water) 67%

156–157 (ethanol/water) 64%

153–154(lit. 154–155)(ethanol/water)80%

147–148 (ethanol/water) 72%

142–143 (ethanol/water) 63%

179–180 (ethanol/water) 73%

162–164 (ethanol/water) 22%

148–150 (ethanol/water) 39%

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

2-CH₃OPh

2-Thienyl

3-Thienyl

2-Furyl

COOEt

Me

H

C₁₆H₁₃N₄O₃Cl (344.74)

C₁₃H₉N₄O₂SCl (320.75)

C₁₃H₉N₄O₃Cl (304.69)

7 ^b

8

9

C

₁₈H₁₅N₄O₄Cl (386.80)

C₁₁H₈N₅O₂Cl (277.67)

C₁₀H₉N₄O₂Cl (252.65)

C₁₅H₁₂N₄O₂(280.3)

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

C₁₅H₁₁N₄O₂Cl (314.74)

C₁₅H₁₁N₄O₂F (298.28)

C₁₅H₁₀N₄O₂ClF (332.72)

C₁₅H₁₁N₄O₂F (298.28)

C₁₅H₁₀N₄O₂ClF (332.72)

C₁₅H₁₁N₄O₂F (298.28)

C₁₅H₁₀N₄O₂ClF (332.72)

C₁₅H₁₁N₄O₂Cl (314.74)

C₁₅H₁₀N₄O₂Cl₂(349.18)

C₁₅H₁₁N₄O₂Cl (314.74)

C₁₅H₁₀N₄O₂Cl₂(349.18)

C₁₅H₁₁N₄O₂Cl (314.74)

C₁₅H₁₀N₄O₂Cl₂(349.18)

C₁₅H₉N₄O₂Cl₃(383.62)

C₁₄H₁₁N₅O₂(281.28)

H

2-Py

Cl

C₁₄H₁₀N₅O₂Cl (315.72)

^aFor compounds 11 and 23 see Ref. [19].

^bIsolated as iminoderivative.

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

377

Table 2

Chemical data for pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides

a

Comp.

R (2)

R% (3)

R%% (8)

Formula (MW)

M.p. (°C) (recrystallization solvent) yield

1a

2a

1b

2b

1c

2c

1d

2d

3a

3e

4a

4f

5a

5e

5g

6a

6e

7a

7f

7h

8a

8d

9a

9b

Ph

CN

H

Cl

H

Cl

H

Cl

H

C₁₆H₉N₅O (287.29)

239–240 (methoxyethanol) 77%

281–282 (methoxyethanol) 62%

271–272 (methoxyethanol) 50%

273–274 (methoxyethanol) 38%

253–255 (acetic acid 50%) 25%

255–256 (methoxyethanol) 70%

239–240 (ethanol) 40%

C₁₆H₈N₅OCl (321.75)

C₁₆H₁₁N₅O₂(305.21)

C₁₆H₁₀N₅O₂Cl (339.73)

C₁₆H₁₀N₄O₃(306.28)

C₁₆H₉N₄O₃Cl (340.80)

C₁₈H₁₄N₄O₃(334.33)

C₁₈H₁₃N₄O₃Cl (368.78)

C₁₅H₉N₄OCl (296.72)

C₁₅H₈N₄O₂ClBr (375.74)

C₁₆H₁₁N₄O₂Cl (326.73)

C₁₆H₉N₄O₂ClBr₂(484.55)

C₁₃H₇N₄OSCl (302.73)

C₁₃H₆N₄OSClBr (381.53)

C₁₃H₃N₄OSClBr₄(618.34)

C₁₃H₇N₄OSCl (302.73)

C₁₃H₆N₄OSClBr (381.53)

C₁₃H₇N₄O₂Cl (286.69)

CONH₂

COOH

COOEt

H

Br

H

Br

H

Br

H

Br

H

Br

H

Ph

CN

CONH₂

COOH

COOEt

H

Br

Ph

2-FPh

3-FPh

4-FPh

2-ClPh

3-ClPh

4-ClPh

3,4-diClPh

2-Py

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

190–191 (ethanol) 50%

Ph

268–269 (methoxyethanol) 69%

293–294 (methoxyethanol) 95%

282–284 (methoxyethanol) 74%

269–270 (methoxyethanol) 50%

232–233 (methoxyethanol) 65%

257–258 (methoxyethanol) 55%

262–263 (ethanol) 30%

235–236 (methoxyethanol) 65%

244–245 (methoxyethanol) 53%

223–224 (ethanol) 85%

2-CH₃OPh

2-CH₃O-5-BrPh

2-thienyl

3,4,5-triBrthien-2-yl

3-thienyl

2-furyl

3-Brfur-2-yl

C₁₃H₅N₄O₂ClBr₂(444.25)

260–261 (methoxyethanol) 45%

226–227 (ethanol) 20%

285–286 (ethanol) 77%

C₁₃H₆N₄O₂ClBr (365.64)

C₁₆H₉N₄O₃Cl (340.80)

COOH

COOEt

Me

H

C₁₈H₁₃N₄O₃Cl (368.78)

214–215 (ethanol) 78%

C₁₁H₆N₅OCl (259.65)

C₁₁H₈N₅O₂Cl (295.69)

C₁₁H₇N₄O₃Cl (278.65)

239–240 (isopropanol) 46%

283–284 (methoxyethanol) 40%

288–290 (isopropanol) 37%

200–201 (isopropanol) 70%

199–200 (isopropanol) 60%

206–209 (isopropanol) 65%

216–217(lit. 213–214)(ethanol) 82%

229–230 (methoxyethanol) 50%

228–229 (ethanol) 92%

9c

9d

C₁₃H₁₁N₄O₃Cl (306.60)

10a

10e

11a

12a

13a

14a

15a

16a

17a

18a

19a

20a

21a

22a

23a

24a

25a

26a

27a

28a

C₁₀H₇N₄OCl (234.63)

C₁₀H₆N₄OClBr (313.54)

C₁₅H₁₀N₄O (262.28)

C₁₅H₉N₄OCl (296.72)

C₁₅H₉N₄OF (280.27)

C₁₅H₈N₄OClF (314.71)

229–230 (ethanol) 73%

235–236 (ethanol) 75%

244–245 (ethanol) 50%

C

₁₅H₉N₄OF (280.27)

C₁₅H₈N₄OClF (314.71)

₁₅H₉N₄OF (280.27)

C

243–244 (methoxyethanol) 86%

263–264 (methoxyethanol) 78%

203–204 (methoxyethanol) 78%

247–248 (methoxyethanol) 56%

236–237 (methoxyethanol) 70%

256–257 (methoxyethanol) 54%

240–241(lit. 236–37) (methoxyethanol) 70%

269–270 (methoxyethanol) 70%

249–251 (methoxyethanol) 77%

280–238 (methoxyethanol) 76%

251–252 (methoxyethanol) 84%

274–275 (methoxyethanol) 43%

C₁₅H₈N₄OClF (314.71)

C₁₅H₉N₄OCl (296.72)

C₁₅H₈N₄OCl₂(331.16)

C₁₅H₉N₄OCl (296.72)

C₁₅H₈N₄OCl₂(331.16)

C₁₅H₉N₄OCl (296.72)

C₁₅H₈N₄OCl₂(331.16)

C₁₅H₇N₄OCl₃(365.60)

C₁₄H₉N₅O (263.62)

H

2-Py

Cl

C₁₄H₈N₅OCl (297.70)

^aFor compounds 11a and 23a see Ref. [19].

converted into the ethyl ester with thionyl chloride

and absolute ethanol (1d, 2d and 9d). Compounds

3a–7a and 10a were transformed in 3-bromoderiva-

tives, required by the SAR study. By treatment with a

solution of an equimolar amount of bromine in chlo-

roform, compound 3e from 3a, the dibromoderiva-

378

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

Scheme 1.

Scheme 2.

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

379

Table 3

BZR ligand afﬁnity of pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides

Comp

R (2)

R% (3)

R%% (8)

% Inhibition^a

K_i(nM)^b

GR^c

1a

2a

1d

2d

3a

3e

4a

4f

5e

6e

7a

7f

8d

9a

9d

10a

10e

11a

12a

13a

14a

15a

16a

17a

18a

19a

20a

21a

22a

23a

24a

25a

26a

27a

28a

29^d

30^d

31^d

Ph

CN

COOEt

H

Br

H

Br

H

Br

Ph

CN

COOEt

H

Br

Ph

H

Cl

H

390.15

3.990.16

6.190.52

1090.91

0

47.292.79

0

31.792.52

0

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

2-CH₃OPh

2-CH₃O-5-BrPh

2-thienyl

3-thienyl

2-furyl

3-Brfur-2-yl

COOEt

Me

H

0

2591.90

6194.80

4192.70

3591.80

6296.4

36.792.8

0

8.690.72

690.42

1190.93

5.190.40

0

Ph

2-FPh

3-FPh

4-FPh

2-ClPh

3-ClPh

4-ClPh

3,4-diClPh

2-Py

COOEt

Br

0

10.490.73

190.05

0

490.25

2091.3

3592.10

99.895.0

9893.2

9691.0

3592.0

12094.5

3429

1.91

1.31

1.37

CN

^a% Inhibition of speciﬁc [³H]Ro15-1788 ([³H]Flunitrazepam for 29, 30, 31) binding at 10 mM concentration are means 9SEM of ﬁve

determinations.

^bK_ivalues are means 9SEM of ﬁve determinations.

^cGR (GABA ratio)=IC₅₀(compound)/+IC₅₀(compound+10 mM GABA).

^dRefs. [1,2].

tive 4f from 4a, compound 5e from 5a, 6e from 6a, and

10e from 10a were obtained. Tetrabromoderivative 5g

from 5a was obtained, if the reaction was carried out

with a molar ratio 1/5 (substrate/bromine). Compound

7a treated with either an equivalent amount or an

excess of bromine gave a mixture of three brominated

compounds in both cases: the 2-(3-bromofur-2-yl)-3-

bromo-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine

5-

oxide (7f), the 2-(3-bromofur-2-yl)-8-chloropyrazolo-

[5,1-c][1,2,4]benzotriazine 5-oxide (7h) (separates by

column chromatography) and traces of 2-(fur-2-yl)-3-

bromo-8-chloro-pyrazolo[5,1-c][1,2,4]benzotriazine 5-

oxide, only identiﬁed by spectroscopical means in the

reaction mixture.

380

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

3. Biological results and discussion

The BZR binding afﬁnity of pyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxides was evaluated by their ability to

displace [³H]Ro15-1788 from its speciﬁc binding in

bovine brain membranes.

Binding data for all new compounds and of the

reference compounds (29, 30, 31) [2] are listed in Table

3.

As shown in Table 3, the new synthesized pyra-

zolo[5,1-c][1,2,4]benzotriazine 5-oxides display insigniﬁ-

cant or no afﬁnity for BZR. From these results the

following observations arise.

Fig. 3. Overlay of 3-phenyl-8-chloropyrazolo[5,1-c][1,2,4]benzotriaz-

ine 5-oxide (12a) (black line) and (29) (gray line). The lack of ethoxy-

carbonyl group at the 3-position does not support the hydrogen bond

by H₁/N-4 and causes the loss of receptor afﬁnity.

The introduction of a substituent as methyl-, ethoxy-

carbonyl-, heteroaryl- and aryl- at the 2-position (1a,

2a, 1d, 2d, 3a, 3e, 4a, 4f, 5e, 6e, 7f, 8d, 9a, 9d, 10a and

10e) is generally unfavorable for BZR recognition. This

is also true for those compounds bearing, at the 3-posi-

tion, a bromine or ethoxycarbonyl group (1d, 2d, 3e, 4f,

5e, 6e, 7f, 9d and 10e) which were found to be the

suitable substituents for receptor binding (see reference

compounds 29, 30, 31 and Ref. [2]).

The replacement of the 3-ethoxycarbonyl group in

the lead compound 29 by a phenyl ring (11a, 12a) or

ortho-, meta-, para-substituted phenyl ring with elec-

tron-withdrawing atoms (13a–25a) or by a 2-pyridine

(27a–28a) eliminates the receptor recognition, even

though the planar tricyclic moiety of pyrazolo[5,1-c]-

[1,2,4]benzotriazine 5-oxide is unchanged.

Fig. 1. Interaction of 3-ethoxycarbonyl-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (29), at the proposed qualitative model for

recognition at the BZR. Hydrogen bonds involving H₁and H₂by

means N–4/CO and N-1 are labeled.

Comparison of BZR afﬁnity of 29, 30 and 31 with

new compounds suggests that the lack of afﬁnity of

these latter compounds could be due to a steric prob-

lem and/or an inefﬁcient formation of the hydrogen

bond with the receptor protein.

In the attempt to explain the better ﬁtting of 29 with

BZR, a qualitative pharmacophore/receptor model was

carried out by active analog approach [6]. A total of 12

molecules were selected as the training set. These com-

pounds span a great range of afﬁnity values to BZR (1

nMBK_iB1000 nM) and belong to chemically different

classes such as b-carboline, diazepines, pyrazoloquinoli-

nes, pyrazolopyrimidines. Among the molecules of the

training set used for building the qualitative BZR

model, there is the lead molecule 3-ethoxycarbonyl-8-

chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (29).

From this qualitative model, three hydrogen bond

Fig. 2. Superimposition of 2-phenyl-3-ethoxycarbonyl-8-chloropyra-

zolo[5,1-c][1,2,4]benzotriazine 5-oxide (2d) (black line) and (29) (gray

line). The hydrogen bond sites and an overlay between the 2-phenyl

ring of 2d and a steric region of the BZR protein are evidenced.

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

381

this substituent is an ethoxycarbonyl group, as in the

lead molecule 29, the lone pair orientation of car-

bonyl oxygen of the estereal chain can reinforce the

receptor binding by means of a three-centered hydro-

gen bond. The 5-oxide group also has an important

role to reinforce this hydrogen bond, as in compound

30.

The substituent at the 2-position can interact with

a steric hindrance region and does not permit the

ligand interaction with the receptor protein.

Current studies are now in progress to verify the

validity of the above proposed pharmacophore model

and in particular to conﬁrm the ﬁtting of the 3-sub-

stituent in the lipophilic pockets (L₁/L₂). Moreover,

to better deﬁne the features, size and location of

these lipophilic pockets (L₁/L₂), the synthesis of new

pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides bearing in

the 3-position estereal, ethereal, ketonic group or

isoster rings to esteric function, are now in progress.

points and areas of negative steric interaction have

been characterized, as previously reported. These

pharmacophoric descriptors can be designated as H₁

and H₂for the hydrogen donor sites, S₁and S₂for

the repulsive steric interaction regions and L₁, L₂and

L₃for the lipophilic regions [3,7–12] (see Figs. 1–3

for the sake of clarity).

As shown in Fig. 1, the afﬁnity of 29 (K_i=35 nM,

GR=1.91 [2]) may be explained since it interacts at

the receptor site with N-1 and N-4 by means of hy-

drogen bond involving H₂and H₁donor sites, respec-

tively. Moreover, the hydrogen bond N-4/H₁is also

reinforced by the presence of the carbonyl group of

the estereal chain, forming a three-centered hydrogen

,

bond (hydrogen bond length CO/H₁2.10 A). Further-

more, the 5-oxide group can reinforce N-4 binding.

The alignment of ligand 29 in the pharmacophore/re-

ceptor model shows that the ethoxycarbonyl group

seems to occupy the lipophilic region L₁/L₂.

According to this model, the above suggested hy-

potheses to explain the inactivity of new compounds

are plausible.

4. Experimental

In fact, choosing compounds 2d and 12a as repre-

sentative of the series of the 2- or 3-arylpyrazolo[5,1-

c][1,2,4]benzotriazine 5-oxides and overlaying them on

compound 29, the following remarks on the SAR can

be made:

4.1. Chemistry

The structure of all compounds were supported by

their IR spectra (KBr pellets in Nujol mulls, Perkin–

Elmer 681 spectrophotometer) and ¹H NMR data

(measured with a Varian Gemini at 200 MHz; chemi-

cal shifts are expressed in l (ppm) using DMSO-d₆or

CDCl₃as solvent). Melting points were determined

with a Gallenkamp apparatus and are uncorrected.

Elemental analyses were performed by the laborato-

ries of Dipartimento Farmaco-Chimico-Tecnologico

of the University of Siena, Italy, with a Perkin–

Elmer, model 240C, Elemental Analyzer and their re-

sults are within 90.4% of theoretical values. The

purity of samples was determined by means of TLC,

which was performed using Machery–Nagel Duren,

Alugram silica-gel plates.

The presence of an overlay between the 2-phenyl

ring of 2d and a steric hindrance region of the

BZR protein causes a distortion of the molecule

with loss of alignment for N-4/H₁and CO/H₁, re-

quired for hydrogen bond formation (Fig. 2).

In the superimposition of 12a and 29, although the

hindrance of the 3-phenyl ring and the ethoxycar-

bonyl group are almost the same, the loss of recep-

tor afﬁnity may be explained by the lack of an

ethoxycarbonyl group which exhibits a supporting

function to N-4/H₁hydrogen bond formation.

Moreover, the 3-phenyl ring, which would cause

the shift of the whole molecule, does not allow the

5-oxide/H₁hydrogen bond to be formed to give its

contribution to the receptor afﬁnity (Fig. 3). On

the other hand, this situation is permitted when a

less hindering group, such as a bromine, is present

in the 3-position, as in 3-bromo-8-chloropyra-

zolo[5,1-c][1,2,4]benzotriazine 5-oxide (30) (see

Table 3).

4.2. General procedure for synthesis of

3-oxopropanenitriles

A suspension of 50% sodium hydride in mineral oil

was added to anhydrous toluene (300 ml) in a 1 l

round bottomed ﬂask. After addition of tert-amyl al-

cohol (2 ml) the mixture was heated at 70°C and a

solution of a commercially available suitable acetoni-

trile derivative (200 mmol) and ethyl formate (200

mmol, 17 ml) in anhydrous toluene (50 ml), was

added dropwise over a period of 60 min. After 6 h of

stirring and heating at 70–80°C, the resulting solid

was allowed to stand overnight. The mixture was

treated with ice-cold water (400 ml) and the aqueous

phase was separated and washed with diethyl ether.

In conclusion, structure–activity relationships

(SARs) indicate that these pyrazolo[5,1-c][1,2,4]-

benzotriazine ligands bind to BZR with N-1 and N-4

by means of a hydrogen bond involving the H₂and

H₁donor sites, respectively, the substituent at 3-posi-

tion, critical for steric hindrance and lipophilic fea-

ture, ﬁts into lipophilic region L₁/L₂. In particular, if

382

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

Acidiﬁcation with conc. hydrochloric acid caused the

4.8. 1-(2-Nitrophenyl)-3-phenyl-5-aminopyrazole-4-car-

bonitrile (1)

separation of an oil which was extracted with diethyl

ether. The extracts were dried on anhydrous sodium

sulfate, evaporated to dryness and a solid residue was

obtained.

From 2-nitrophenylhydrazine and phenylmethoxy-

methylenemalononitrile. Yellow crystals; TLC eluent

cyclohexane/ethyl acetate 2/1; IR w (cm⁻¹): 3405–3238,

1

4.3. 2-(2%-Fluorophenyl)-3-oxopropanenitrile

2217, 1360; H NMR (CDCl₃): l 8.10 (d, 1H, H-3%),

7.75 (m, 3H, H-4%, H-5%, H-6% and 2H 3-Ph), 7.40 (m,

This compound was obtained from 2-(2%-ﬂuoro-

phenyl)acetonitrile. Yellow crystals, yield 74%; m.p.

130°C after recrystallization from ethanol/water; IR w

3H, 3-Ph), 4.58 (s, 2H, NH₂).

4.9. 1-(2-Nitro-5-chlorophenyl)-3-phenyl-5-amino-

pyrazole-4-carbonitrile (2)

1

(cm⁻¹): 2210, 1650; H NMR (DMSO-d₆): l 12.20 (s,

1H, OH, exch.), 7.84 (s, 1H, CHO), 7.72 (s, 1H, CH),

7.20–7.46 (m, 4H, Ph). Anal. C₉H₆NOF (C, 1H, N).

From 2-nitro-5-chlorophenylhydrazine and phenyl-

methoxymethylenemalononitrile. Orange crystals; TLC

eluent cyclohexane/ethyl acetate 2/1; IR w (cm⁻¹):

3480–3100, 2210, 1370; H NMR (CDCl₃): l 8.08 (d,

1H, H-3%), 7.90 (m, 2H, 3-Ph), 7.68 (m, 2H, H-4% and

H-6%), 7.45 (m, 3H, 3-Ph), 4.51 (s, 2H, NH₂).

4.4. 2-(3%-Fluorophenyl)-3-oxopropanenitrile

1

This compound was obtained from 2-(3%-ﬂuoro-

phenyl)acetonitrile. Yellow crystals, yield 77%; m.p.

154°C after recrystallization from ethanol/water; IR w

1

(cm⁻¹): 2210, 1650; H NMR (DMSO-d₆): l 12.40 (s,

4.10. 1-(2-Nitro-5-chlorophenyl)-3-methyl-5-amino-

pyrazole-4-carbonitrile (9)

1H, OH, exch.), 8.16 (s, 1H, CHO), 7.76 (s, 1H, CH),

7.06–7.59 (m, 4H, Ph). Anal. C₉H₆NOF (C, 1H, N).

From 2-nitro-5-chlorophenylhydrazine and ethyl-

ethoxymethylenemalononitrile. Yellow crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 3410–3330, 2219; ¹H NMR (CDCl₃): l 8.04 (d,

1H, H-3%), 7.64 (dd, 1H, H-4%), 7.62 (d, 1H, H-6%), 4.45

(bs, 2H, NH₂), 2.30 (s, 3H, CH₃).

4.5. 2-(4%-Fluorophenyl)-3-oxopropanenitrile

This compound was obtained from 2-(4%-ﬂuoro-

phenyl)acetonitrile. Yellow crystals, yield 80%; m.p.

150–151°C after recrystallization from ethanol/water;

IR w (cm⁻¹): 2210, 1650; ¹H NMR (DMSO-d₆): l 12.25

(s, 1H, OH, exch.), 8.08 (s, 1H, CHO), 7.65–7.76 (m,

2H, Ph, CH), 7.53–7.58 (m, 1H, Ph), 7.20–7.47 (m, 2H,

Ph). Anal. C₉H₆NOF (C, 1H, N).

4.11. 1-(2-Nitro-5-chlorophenyl)-3-methyl-5-amino-

pyrazole (10)

From 2-nitro-5-chlorophenylhydrazine and 2-amino-

4.6. 2-(2-Pyridyl)-3-oxopropanenitrile

crotononitrile. Yellow crystals; TLC eluent toluene/

1

ethyl acetate 8/2; IR w (cm⁻¹): 3320–3280, 1360; H

This compound was obtained from 2-(2-pyridyl)-

acetonitrile. Yellow crystals, yield 67%; m.p. 184–

188°C after recrystallization from ethyl acetate/cyclo-

NMR (CDCl₃): l 7.94 (d, 1H, H-3%), 7.64 (dd, 1H,

H-6%), 7.48 (d, 1H, H-4%), 5.50 (s, 1H, CH), 3.55 (bs, 2H,

NH₂), 2.20 (s, 3H, CH₃).

hexane; IR

w

(cm⁻¹): 2190, 1630; ¹H NMR

(DMSO-d₆): l 9.08 (s, 1H, CHO), 8.28–8.34 (m, 1H,

H-6 Py), 8.04–8.16 (m, 1H, H-5 Py), 7.18–7.34 (m, 2H,

H-3 and H-4 Py). Anal. C₈H₆N₂O (C, 1H, N).

4.12. General procedure for the synthesis of 3–8,

11–28

4.7. General procedure for the synthesis of 1, 2, 9 and

10

A solution of the suitable aroylacetonitrile [15,16] or

ethyl 2-oxo-3-phenyl-3-cyanopropionate [17] or 3-oxo-

propanenitrile 2-substituted (0.01 mmol) [18] and 2-ni-

tro-5-chlorophenylhydrazine or 2-nitrophenylhydrazine

(0.01 mmol), were dissolved in ethanol (100 ml) with

conc. hydrochloric acid as catalyst. Compounds 27 and

28 were obtained from suitable oxopropanenitrile (0.91

mmol) using acetic acid as catalyst and the reaction

time was 60 h. The ﬁnal solution was evaporated to

dryness and the residue, neutralized with 10% sodium

hydroxide, was ﬁltered and puriﬁed by a suitable

solvent.

A solution of suitable 5-nitrophenylhydrazine or 2-

nitro-5-chlorophenylhydrazine (4.5 mmol), phenyl-

methoxymethylenemalononitrile [13], or ethylethoxy-

methylenemalononitrile [14], or 3-aminocrotononitrile

(5.4 mmol) in ethanol (60 ml) with acetic acid as

catalyst, was reﬂuxed for 12 h and monitored by TLC.

The ﬁnal solution was evaporated and the residue was

washed with diethyl ether and recrystallized by suitable

solvent.

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

383

4.18. Ethyl 1-(2-Nitro-5-chlorophenyl)-4-phenyl-5-

aminopyrazole-3-carboxylate (8)

4.13. 1-(2-Nitro-5-chlorophenyl)-3-phenyl-5-amino-

pyrazole (3)

From 2-nitro-5-chlorophenylhydrazine and ethyl 2-

oxo-3-phenyl-3-cyanopropionate. Yellow crystals; TLC

eluent chloroform/methanol 10/1; IR w (cm⁻¹): 3440–

From benzoylacetonitrile and 2-nitro-5-chlorophenyl-

hydrazine. Yellow crystals; TLC eluent carbon tetra-

chloride/methanol 10/0.5; IR w (cm⁻¹): 3420–3280,

1

3360, 1710; H NMR (DMSO-d₆): l 8.25 (d, 1H, H-3%),

1360; H NMR (CDCl₃): l 7.98 (d, 1H, H-3%), 7.75 (m,

8.00 (d, 1H, H-6%), 7.90 (dd, 1H, H-4%), 7.25–7.35 (m,

5H, 4-Ph), 5.55 (bs, 2H, NH₂), 4.18 (q, 2H, CH₂), 1.15

(t, 3H, CH₃).

3H, H-2, H-6 of 3-Ph, H-6%), 7.52 (dd, 1H, H-4%), 7.38

(m, 3H, H-3, H-4 and H-5 of 3-Ph), 6.02 (s, 1H, H-4),

3.68 (s, 2H, NH₂).

4.19. 1-(2-Nitrophenyl)-4-phenyl-5-aminopyrazole (11)

4.14. 1-(2-Nitro-5-chlorophenyl)-3-(2-methoxyphenyl)-

5-aminopyrazole (4)

From2-phenyl-3-oxopropanenitrileand2-nitrophenyl-

hydrazine. Yellow crystals; TLC eluent toluene/

From 2-methoxybenzoylacetonitrile and 2-nitro-5-

chlorophenylhydrazine. Yellow crystals; TLC eluent cy-

clohexane/ethyl acetate 2/1; IR w (cm⁻¹): 3410–3300,

1

ethyl acetate 2/1; IR w (cm⁻¹): 3440–3300, 1360; H

NMR (CDCl₃): l 8.00 (d, 1H, H-3%), 7.70 (m, 4H, H-3,

H-5%, H-6% and 1H of 4-Ph), 7.45 (m, 4H, 4-Ph), 7.26

(t, 1H, H-4%), 3.88 (s, 2H, NH₂).

1

1340; H NMR (CDCl₃): l 7.92 (m, 2H, H-3% and H-6

of 3-Ph), 7.74 (d, 1H, H-6%), 7.50 (dd, 1H, H-4%), 7.30 (t,

1H, H-4 of 3-Ph), 6.95 (t, 2H, H-3 and H-5 of 3-Ph),

6.30 (s, 1H, H-4), 3.90 (s, 3H, OCH₃), 3.68 (s, 2H,

NH₂).

4.20. 1-(2-Nitro-5-chlorophenyl)-4-phenyl-5-amino-

pyrazole (12)

From 2-phenyl-3-oxopropanenitrile and 2-nitro-5-

chlorophenylhydrazine. Yellow crystals; TLC eluent cy-

clohexane/ethyl acetate 2/1; IR w (cm⁻¹): 3440–3300,

4.15. 1-(2-Nitro-5-chlorophenyl)-3-(2-thienyl)-5-amino-

pyrazole (5)

1

1360; H NMR (CDCl₃): l 7.98 (d, 1H, H-3%), 7.70 (m,

From 2-thenoylacetonitrile and 2-nitro-5-chloro-

phenylhydrazine. Yellow crystals; TLC eluent toluene/

ethyl acetate/acetic acid 8/2/1; IR w (cm⁻¹): 3400–3300,

2H, H-3, H-6%), 7.55 (dd, 1H, H-4%), 7.42 (m, 5H, 4-Ph),

3.88 (s, 2H, NH₂).

1

4.21. 1-(2-Nitrophenyl)-4-(2-ﬂuorophenyl)-5-amino-

pyrazole (13)

1340; H NMR (CDCl₃): l 8.00 (d, 1H, H-3%), 7.71 (d,

1H, H-6%), 7.55 (dd, 1H, H-4%), 7.31 (dd, 1H, H-3%% thio),

7.25 (m, 1H, H-5%% thio.), 7.04 (t, 1H, H-4%% thio.), 5.95

(s, 1H, H-4), 3.65 (s, 2H, NH₂).

From 2-(2-ﬂuorophenyl)-3-oxopropanenitrile and 2-

nitrophenylhydrazine. Orange crystals; TLC eluent car-

bon tetrachloride/methanol 10/0.5; IR

w

(cm⁻¹):

4.16. 1-(2-Nitro-5-chlorophenyl)-3-(3-thienyl)-5-amino-

pyrazole (6)

1

3420–3380, 1360; H NMR (DMSO-d₆): l 8.11 (d, 1H,

H-3%), 7.50–7.80 (m, 5H, H-3, H-4%, H-5%, H-6% and 1H

of 4-Ph), 7.26 (m, 3H, 4-Ph), 5.53 (s, 2H, NH₂).

From 3-thenoylacetonitrile and 2-nitro-5-chloro-

phenylhydrazine. Yellow crystals; TLC eluent toluene/

4.22. 1-(2-Nitro-5-chlorophenyl)-4-(2-ﬂuorophenyl)-5-

aminopyrazole (14)

1

ethyl acetate 8/2; IR w (cm⁻¹): 3400–3300, 1350; H

NMR (CDCl₃): l 7.98 (d, 1H, H-3%), 7.72 (d, 1H, H-6%),

7.55 (m, 2H, H-4% and H-2%% thio.), 7.45 (dd, 1H, H-5%%

thio.), 7.32 (dd, 1H, H-4%% thio.), 5.95 (s, 1H, H-4), 3.65

(s, 2H, NH₂).

From 2-(2-ﬂuorophenyl)-3-oxopropanenitrile and 2-

nitro-5-chlorophenylhydrazine. Yellow crystals; TLC

eluent carbon tetrachloride/methanol 10/0.5; IR w

(cm⁻¹): 3300–3160, 1360; ¹H NMR (CDCl₃): l 8.00 (d,

1H, H-3%), 7.73 (m, 2H, H-3, H-6%), 7.58 (dd, 1H, H-4%),

7.47 (t, 1H, 4-Ph), 7.23(m, 3H, 4-Ph), 3.89 (s, 2H,

NH₂).

4.17. 1-(2-Nitro-5-chlorophenyl)-3-(2-furyl)-4H-5-

iminopyrazole (7)

From 2-furoylacetonitrile and 2-nitro-5-chloro-

phenylhydrazine and isolated as iminopyrazole. Orange

crystals; TLC eluent cyclohexane/ethyl acetate 1/2; IR w

4.23. 1-(2-Nitrophenyl)-4-(3-ﬂuorophenyl)-5-amino-

pyrazole (15)

1

(cm⁻¹): 3300, 1330; H NMR (CDCl₃): l 12.61(s, 1H,

NH), 8.15 (d, 1H, H-3%), 8.03 (d, 1H, H-6%), 7.79 (d, 1H,

H-3%% fur.), 6.95 (d, 1H, H-5%% fur.), 6.88 (dd, 1H, H-4%),

6.67 (dd, 1H, H-4%% fur.), 3.80 (s, 2H, CH₂).

From 2-(3-ﬂuorophenyl)-3-oxopropanenitrile and 2-

nitrophenylhydrazine. Yellow crystals; TLC eluent

toluene/ethyl acetate/acetic acid 8/2/1; IR w (cm⁻¹):

384

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

1

3300–3200, 1360; H NMR (DMSO-d₆): l 8.11 (d, 1H,

H-3%), 7.77 (m, 4H, H-3, H-4%, H-5%, H-6%), 7.37 (m, 3H,

4-Ph), 6.98 (t, 1H, 4-Ph), 5.72 (s, 2H, NH₂).

4.29. 1-(2-Nitrophenyl)-4-(3-chlorophenyl)-

5-aminopyrazole (21)

From 2-(3-chlorophenyl)-3-oxopropanenitrile and 2-

nitrophenylhydrazine. Yellow crystals; TLC eluent

toluene/ethyl acetate/acetic acid 8/2/1; IR w (cm⁻¹):

4.24. 1-(2-Nitro-5-chlorophenyl)-4-(3-ﬂuorophenyl)-

5-aminopyrazole (16)

1

3420–3400; H NMR (DMSO-d₆): l 8.11 (d, 1H, H-3%),

7.80 (m, 4H, H-3, H-4%, H-5%, H-6%), 7.47 (m, 3H, 4-Ph),

7.21 (dd, 1H, 4-Ph), 5.73 (s, 2H, NH₂).

From 2-(3-ﬂuorophenyl)-3-oxopropanenitrile and 2-

nitro-5-chlorophenylhydrazine. Yellow crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 3300–3180, 1360; ¹H NMR (DMSO-d₆): l 8.15

(d, 1H, H-3%), 7.83 (m, 3H, H-3, H-4%, H-6%), 7.38 (m,

2H, 4-Ph), 6.99 (m, 2H, 4-Ph), 5.87 (s, 2H, NH₂).

4.30. 1-(2-Nitro-5-chlorophenyl)-4-(3-chlorophenyl)-

5-aminopyrazole (22)

From 2-(3-chlorophenyl)-3-oxopropanenitrile and 2-

nitro-5-chlorophenylhydrazine. Yellow crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

4.25. 1-(2-Nitrophenyl)-4-(4-ﬂuorophenyl)-5-

aminopyrazole (17)

1

(cm⁻¹): 3290–3160; H NMR (DMSO-d₆): l 8.15 (d,

1H, H-3%), 7.88 (d, 1H, H-6%), 7.80 (m, 2H, H-3, H-4%),

7.47 (m, 3H, 4-Ph), 7.22 (dd, 1H, 4-Ph), 5.87 (s, 2H,

NH₂).

From 2-(4-ﬂuorophenyl)-3-oxopropanenitrile and 2-

nitrophenylhydrazine. Yellow crystals; TLC eluent

toluene/ethyl acetate/acetic acid 8/2/1; IR w (cm⁻¹):

3300–3180, 1360; H NMR (DMSO-d₆): l 8.10 (d, 1H,

H-3%), 7.77 (m, 4H, H-3, H-4%, H-5%, H-6%), 7.56 (m, 2H,

1

4.31. 1-(2-Nitrophenyl)-4-(4-chlorophenyl)-

5-aminopyrazole (23)

4-Ph), 7.21 (m, 2H, 4-Ph), 5.56 (s, 2H, NH₂).

From 2-(4-chlorophenyl)-3-oxopropanenitrile and 2-

nitrophenylhydrazine. Yellow crystals; TLC eluent

toluene/ethyl acetate/acetic acid 8/2/1; IR w (cm⁻¹):

3400–3290, 1360; H NMR (DMSO-d₆): l 8.10 (d, 1H,

H-3%), 7.76 (m, 4H, H-3, H-4%, H-5%, H-6%), 7.48 (m, 4H,

4.26. 1-(2-Nitro-5-chlorophenyl)-4-(4-ﬂuorophenyl)-

5-aminopyrazole (18)

1

From 2-(4-ﬂuorophenyl)-3-oxopropanenitrile and 2-

nitro-5-chlorophenylhydrazine. Yellow crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 3390–3360, 1360; ¹H NMR (DMSO-d₆): l 8.14

(d, 1H, H-3%), 7.89 (d, 1H, H-6%), 7.81 (m, 2H, H-3,

H-4%), 7.54 (m, 2H, 4-Ph), 7.24 (m, 2H, 4-Ph), 5.72 (s,

2H, NH₂).

4-Ph), 5.66 (s, 2H, NH₂).

4.32. 1-(2-Nitro-5-chlorophenyl)-4-(4-chlorophenyl)-5-

aminopyrazole (24)

From 2-(4-chlorophenyl)-3-oxopropanenitrile and 2-

nitro-5-chlorophenylhydrazine. Yellow crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

4.27. 1-(2-Nitrophenyl)-4-(2-chlorophenyl)-

5-aminopyrazole (19)

1

(cm⁻¹): 3460–3375; H NMR (DMSO-d₆): l 8.14 (d,

1H, H-3%), 7.88 (d, 1H, H-6%), 7.79 (m, 2H, H-3, H-4%),

7.49 (m, 4H, 4-Ph), 5.82 (s, 2H, NH₂).

From 2-(2-chlorophenyl)-3-oxopropanenitrile and 2-

nitrophenylhydrazine. Yellow crystals; TLC eluent

toluene/ethyl acetate/acetic acid 8/2/1; IR w (cm⁻¹):

3420–3360, 1360; H NMR (DMSO-d₆): l 8.08 (d, 1H,

H-3%), 7.83 (m, 3H, H-4%, H-5%, H-6%), 7.54 (s, 1H, H-3),

4.33. 1-(2-Nitrophenyl)-4-(3,4-dichlorophenyl)-5-amino-

pyrazole (25)

1

7.41 (m, 4H, 4-Ph), 5.43 (s, 2H, NH₂).

From 2-(3,4-dichlorophenyl)-3-oxopropanenitrile and

2-nitrophenylhydrazine. Yellow crystals; TLC eluent

toluene/ethyl acetate/acetic acid 8/2/1; IR w (cm⁻¹):

4.28. 1-(2-Nitro-5-chlorophenyl)-4-(2-chlorophenyl)-

5-aminopyrazole (20)

1

3420–3380; H NMR (DMSO-d₆): l 8.12 (d, 1H, H-3%),

7.55–7.89 (m, 4H, H-3, H-4%, H-5%, H-6% and 3H of

From 2-(2-chlorophenyl)-3-oxopropanenitrile and 2-

nitro-5-chlorophenylhydrazine. Yellow crystals; TLC

eluent toluene/ethyl acetate/acid acetic 8/2/1; IR w

(cm⁻¹): 3400–3300, 1360; ¹H NMR (DMSO-d₆): l 8.13

(d, 1H, H-3%), 7.90 (d, 1H, H-6%), 7.79 (dd, 1H, H-4%),

7.59 (s, 1H, H-3), 7.54 (dd, 1H, 4-Ph), 7.34 (m, 3H,

4-Ph), 5.60 (s, 2H, NH₂).

4-Ph), 5.83 (s, 2H, NH₂).

4.34. 1-(2-Nitro-5-chlorophenyl)-4-(3,4-dichlorophenyl)-

5-aminopyrazole (26)

From 2-(3,4-dichlorophenyl)-3-oxopropanenitrile and

2-nitro-5-chlorophenylhydrazine. Orange crystals; TLC

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

385

1

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 3480–3390, 1360; ¹H NMR (DMSO-d₆): l 8.15

(d, 1H, H-3%), 7.54–7.88 (m, 3H, H-3, H-4%, H-6% and

3H of 4-Ph), 5.97 (s, 2H, NH₂).

1550, 1250, 1020; H NMR (DMSO-d₆): l 8.42 (m, 2H,

H-6, H-9), 8.18 (dd, 1H, 2-Ph), 7.72 (dd, 1H, H-7), 7.45

(t, 1H, 2-Ph), 7.15 (m, 3H, H-3, 2-Ph), 3.92 (s, 3H,

OCH₃).

4.35. 1-(2-Nitrophenyl)-4-(2-pyridyl)-5-aminopyrazole

(27)

4.41. 2-(2-Thienyl)-8-chloropyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (5a)

From 2-(2-pyridyl)-3-oxopropanenitrile and 2-nitro-

phenylhydrazine. Yellow crystals; TLC eluent ethyl ac-

etate/chloroform 7/3; IR w (cm⁻¹): 3300–3240; ¹H

NMR (DMSO-d₆): l 8.49 (d, 1H, H-3 Py), 8.09 (m, 2H,

H-3, H-3%), 7.78 (m, 5H, H-5 and H-6 Py, H-4%, H-5%,

H-6%), 7.08 (t, 1H, H-4 Py), 6.78 (s, 2H, NH₂).

From compound 5 at room temperature (r.t.). Yel-

low crystals; TLC eluent toluene/cyclohexane/i-propyl

1

ether 2/1/0.5; IR w (cm⁻¹): 1570; H NMR (CDCl₃): l

8.47 (m, 2H, H-6, H-9), 7.60 (dd, 1H, H-3% thio.), 7.58

(dd, 1H, H-7), 7.42 (dd, 1H, H-5% thio.), 7.16 (t, 1H,

H-4% thio.), 6.92 (s, 1H, H-3).

4.36. 1-(2-Nitro-5-chlorophenyl)-4-(2-pyridyl)-5-amino-

pyrazole (28)

4.42. 2-(3-Thienyl)-8-chloropyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (6a)

From 2-(2-pyridyl)-3-oxopropanenitrile and 2-nitro-

5-chlorophenylhydrazine. Yellow crystals; TLC eluent

ethyl acetate/chloroform 7/3; IR w (cm⁻¹): 3280–3240,

From compound 6 at r.t. Yellow crystals; TLC eluent

1

toluene/ethyl acetate 8/2; IR w (cm⁻¹): 1570; H NMR

(CDCl₃): l 8.48 (d, 1H, H-6), 8.42 (d, 1H, H-9), 7.87

(dd, 1H, H-2% thio.), 7.64 (dd, 1H, H-5% thio.), 7.54 (dd,

1H, H-7), 7.46 (dd, 1H, H-4% thio.), 6.90 (s, 1H, H-3).

1

1360; H NMR (DMSO-d₆): l 8.50 (d, 1H, H-3 Py),

8.14 (m, 2H, H-3, H-3%), 7.94 (d, 1H, H-6%), 7.76 (m,

3H, H-5 and H-6 Py, H-4%), 7.10 (t, 1H, H-4 Py), 6.90

(s, 2H, NH₂).

4.43. 2-(2-Furyl)-8-chloropyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (7a)

4.37. General procedure for the synthesis of 1a–28a

From compound 7 at 30–40°C. Dark yellow crystals;

TLC eluent ethyl acetate/cyclohexane/i-propyl ether 2/

A suspension of 1.00 mmol of the suitable 5-

aminopyrazole (1–28) in 30 ml of 10% sodium hydrox-

ide and few ml of diglyme, was stirred for 12–24 h. The

precipitate was ﬁltered and puriﬁed by recrystallization.

1

1/0.5; IR w (cm⁻¹): 1570; H NMR (CDCl₃): l 8.49 (d,

1H, H-6), 8.45 (d, 1H, H-9), 7.59 (d, 1H, H-3% fur.),

7.57 (dd, 1H, H-7), 6.99 (d, 1H, H-5% fur.), 6.98 (s, 1H,

H-3), 6.58 (dd, 1H, H-4% fur.).

4.38. 2-Phenyl-3-cyanopyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (1a)

4.44. 2-Carboxy-3-phenyl-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (8a)

From compound 1 at 60–80°C. Yellow crystals; TLC

eluent cyclohexane/ethyl acetate 2/1; IR w (cm⁻¹):

2225, 1552; H NMR (CDCl₃): l 8.55 (m, 2H, H-6,

H-9), 8.15 (m, 3H, H-8 and 2-Ph), 7.78 (t, 1H, H-7),

7.52 (m, 3H, 2-Ph).

From compound 8 at 50°C. Yellow crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

1

(cm⁻¹): 2800–2500, 1700, 1550; H NMR (DMSO-d₆):

l 8.48 (m, 2H, H-6, H-9), 7.85 (dd, 1H, H-7), 7.55–7.45

(m, 6H, Ph and OH).

4.39. 2-Phenyl-3-cyano-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (2a)

4.45. 2-Methyl-3-cyano-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (9a)

From compound 2 at 60–80°C. Yellow crystals; TLC

eluent cyclohexane/ethyl acetate 2/1; IR w (cm⁻¹):

2210, 1560; H NMR (CDCl₃): l 8.50 (m, 2H, H-6,

From compound 9 at r.t. Yellow crystals; TLC eluent

1

toluene/ethyl acetate 8/2; IR w (cm⁻¹): 2225, 1570; H

H-9), 8.20 (m, 2H, 2-Ph), 7.70 (dd, 1H, H-7), 7.55 (m,

3H, 2-Ph).

NMR (CDCl₃): l 8.46 (d, 1H, H-6), 8.36 (d, 1H, H-9),

7.46 (dd, 1H, H-7), 2.60 (s, 3H, CH₃).

4.40. 2-(2-Methoxyphenyl)-8-chloropyrazolo[5,1-c]-

[1,2,4]benzotriazine 5-oxide (4a)

4.46. 2-Methyl-8-chloropyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (10a)

From compound 4 at 50°C. Yellow crystals; TLC

eluent cyclohexane/ethyl acetate 2/1; IR w (cm⁻¹):

From compound 10 at r.t. Yellow crystals; TLC

1

eluent toluene/ethyl acetate 8/2; IR w (cm⁻¹): 1560; H

386

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

NMR (CDCl₃): l 8.48 (d, 1H, H-6), 8.34 (d, 1H, H-9),

7.50 (dd, 1H, H-7), 6.55 (s, 1H, H-3), 2.55 (s, 3H, CH₃).

H-2), 8.44 (m, 2H, H-6, H-9), 7.85 (m, 3H, H-7, 3-Ph),

7.56 (m, 1H, 3-Ph), 7.20 (t, 1H, 3-Ph).

4.53. 3-(4-Fluorophenyl)pyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (17a)

4.47. 3-Phenylpyrazolo[5,1-c][1,2,4]benzotriazine-

5-oxide (11a)

From compound 17 at 80–90°C. Red crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

From compound 11 at 80–90°C. Red crystals; TLC

eluent chloroform/methanol 10/1; IR w (cm⁻¹): 1570;

¹H NMR (CDCl₃): l 8.58 (d, 1H, H-6), 8.40 (m, 2H,

H-9 and 3-Ph), 7.98 (m, 3H, H-2, H-8, 3-Ph), 7.62 (t,

1H, H-7), 7.40 (m, 3H, 3-Ph).

1

(cm⁻¹): 1580; H NMR (DMSO-d₆): l 8.79 (m, 2H,

3-Ph), 8.42 (m, 2H, H-6, H-9), 8.08 (m, 3H, H-8, 3-Ph),

7.77 (t, 1H, H-7), 7.36 (m, 2H, 3-Ph).

4.54. 3-(4-Fluorophenyl)-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (18a)

4.48. 3-Phenyl-8-chloropyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (12a)

From compound 18 at 40–50°C. Red crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1570; ¹H NMR (DMSO-d₆): l 8.83 (s, 1H,

H-2), 8.42 (m, 2H, H-6, H-9), 8.09 (m, 2H, 3-Ph), 7.80

(dd, 1H, H-7), 7.37 (m, 2H, 3-Ph).

From compound 12 at 40–50°C. Red crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

1

(cm⁻¹): 1560; H NMR (CDCl₃): l 8.50 (d, 1H, H-6),

8.40 (m, 2H, H-2, H-9), 7.95 (d, 2H, 3-Ph), 7.45 (m, 4H,

H-7, 3-Ph).

4.55. 3-(2-Chlorophenyl)pyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (19a)

4.49. 3-(2-Fluorophenyl)pyrazolo[5,1-c][1,2,4]-

benzotriazine- 5-oxide (13a)

From compound 19 at 80–90°C. Orange crystals;

TLC eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1570; ¹H NMR (DMSO-d₆): l 8.62 (s, 1H,

H-2), 8.45 (m, 2H, H-6, H-9), 8.14 (t, 1H, H-8), 7.75 (t,

1H, H-7), 7.64 (m, 2H, 3-Ph), 7.49 (m, 2H, 3-Ph).

From compound 13 at 80–90°C. Red crystals; TLC

eluent carbon tetrachloride/methanol 10/0.5; IR w

1

(cm⁻¹): 1560; H NMR (CDCl₃): l 8.58 (m, 2H, H-2,

H-9), 8.47 (d, 1H, H-6), 8.29 (t, 1H, 3-Ph), 7.99 (t, 1H,

H-8), 7.66 (t, 1H, H-7), 7.28 (m, 3H, 3-Ph).

4.56. 3-(2-Chlorophenyl)-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (20a)

4.50. 3-(2-Fluorophenyl)-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (14a)

From compound 20 at 40–50°C. Orange crystals;

TLC eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1560; ¹H NMR (DMSO-d₆): l 8.65 (s, 1H,

H-2), 8.44 (m, 2H, H-6, H-9), 7.80 (dd, 1H, H-7), 7.74

(dd, 1H, 3-Ph), 7.66 (dd, 1H, 3-Ph), 7.49 (m, 2H, 3-Ph).

From compound 14 at 40–50°C. Red crystals; TLC

eluent carbon tetrachloride/methanol 10/0.5; IR w

1

(cm⁻¹): 1560; H NMR (CDCl₃): l 8.50 (m, 3H, H-2,

H-6, H-9), 8.25 (t, 1H, 3-Ph), 7.60 (dd, 1H, H-7), 7.31

(m, 3H, 3-Ph).

4.57. 3-(3-Chlorophenyl)pyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (21a)

4.51. 3-(3-Fluorophenyl)pyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (15a)

From compound 21 at 80–90°C. Orange crystals;

TLC eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1570; ¹H NMR (DMSO-d₆): l 8.88 (s, 1H,

H-2), 8.43 (m, 2H, H-6, H-9), 8.10 (m, 3H, H-8, 3-Ph),

7.79 (t, 1H, H-7), 7.54 (t, 1H, 3-Ph), 7.41 (dd, 1H,

3-Ph).

From compound 15 at 80–90°C. Red crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1570; ¹H NMR (DMSO-d₆): l 8.86 (s, 1H,

H-2), 8.43 (m, 2H, H-6, H-9), 8.12 (t, 1H, H-8), 7.83

(m, 3H, H-8, 3-Ph), 7.56 (m, 1H, 3-Ph), 7.17 (t, 1H,

3-Ph).

4.58. 3-(3-Chlorophenyl)-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (22a)

4.52. 3-(3-Fluorophenyl)-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (16a)

From compound 22 at 40–50°C. Red crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1570; ¹H NMR (DMSO-d₆): l 8.93 (s, 1H,

H-2), 8.44 (m, 2H, H-6, H-9), 8.05 (m, 2H, 3-Ph), 7.79

(dd, 1H, H-7), 7.53 (t, 1H, 3-Ph), 7.42 (dd, 1H, 3-Ph).

From compound 16 at 40–50°C. Orange crystals;

TLC eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1570; ¹H NMR (DMSO-d₆): l 8.91 (s, 1H,

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

387

4.59. 3-(4-Chlorophenyl)pyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (23a) [19]

4.65. General procedure for the synthesis of 1b, 2b and

9b

From compound 23 [19] at 80–90°C. Orange crys-

tals; TLC eluent toluene/ethyl acetate/acetic acid 8/2/1;

IR w (cm⁻¹): 1560; ¹H NMR (DMSO-d₆): l 8.84 (s, 1H,

H-2), 8.43 (m, 2H, H-6, H-9), 8.09 (m, 3H, H-8, 3-Ph),

7.77 (t, 1H, H-7), 7.58 (m, 2H, 3-Ph).

The products were prepared according to a previ-

ously described procedure [1,2] by treatment with conc.

sulfuric acid of compounds 1a, 2a and 9a, respectively.

4.66. 2-Phenyl-3-carbamoylpyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (1b)

4.60. 3-(4-Chlorophenyl)-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (24a)

From compound 1a. Yellow crystals; TLC eluent

toluene/ethyl acetate 8/2; IR w (cm⁻¹): 3420, 1650,

1540; H NMR (DMSO-d₆): l 8.48 (m, 2H, H-6, H-9),

8.15 (t, 1H, H-8), 7.95 (m, 2H, 2-Ph), 7.78 (m, 2H, H-7,

NH), 7.52 (m, 4H, 2-Ph, NH).

1

From compound 24 at 40–50°C. Red crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1560; ¹H NMR (DMSO-d₆): l 8.90 (s, 1H,

H-2), 8.42 (m, 2H, H-6, H-9), 8.10 (m, 2H, 3-Ph), 7.80

(dd, 1H, H-7), 7.63 (m, 2H, 3-Ph).

4.67. 2-Phenyl-3-carbamoyl-8-chloropyrazolo[5,1-c]-

[1,2,4]benzotriazine 5-oxide (2b)

From compound 2a. Yellow crystals; TLC eluent

cyclohexane/ethyl acetate 2/1; IR w (cm⁻¹): 3420, 1670,

1550; H NMR (DMSO-d₆): l 8.48 (m, 2H, H-6, H-9),

4.61. 3-(3,4-Dichlorophenyl)pyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (25a)

1

7.96 (m, 2H, 2-Ph), 7.84 (dd, 1H, H-7), 7.75 (s, 1H,

NH), 7.52 (m, 4H, 2-Ph, NH).

From compound 25 at 80–90°C. Red crystals; TLC

eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1570; ¹H NMR (DMSO-d₆): l 8.91 (s, 1H,

H-2), 8.43 (m, 2H, H-6, H-9), 8.28 (d, 1H, 3-Ph), 7.98

(m, 2H, H-8, 3-Ph), 7.75 (m, 2H, H-7, 3-Ph).

4.68. 2-Methyl-3-carbamoyl-8-chloropyrazolo[5,1-c]-

[1,2,4]benzotriazine 5-oxide (9b)

From compound 9a. Yellow crystals; TLC eluent

chloroform/methanol 10/1; IR w (cm⁻¹): 3440–3340,

1660, 1570; H NMR (DMSO-d₆): l 8.46 (d, 1H, H-6),

4.62. 3-(3,4-Dichlorophenyl)-8-chloropyrazolo[5,1-c]-

[1,2,4]benzotriazine 5-oxide (26a)

1

8.38 (d, 1H, H-9), 7.80 (dd, 1H, H-7), 7.62 (s, 1H, NH),

7.02 (s, 1H, NH), 2.65 (s, 3H, CH₃).

From compound 26 at 40–50°C. Orange crystals;

TLC eluent toluene/ethyl acetate/acetic acid 8/2/1; IR w

(cm⁻¹): 1565; ¹H NMR (DMSO-d₆): l 8.95 (s, 1H,

H-2), 8.45 (m, 2H, H-6, H-9), 8.30 (d, 1H, 3-Ph), 8.05

(dd, 1H, 3-Ph), 7.80 (m, 2H, H-7, 3-Ph).

4.69. General procedure for the synthesis of 1c, 2c and

9c

The products were prepared following an already

known method [1,2] by treatment with conc. sulfuric

acid and sodium nitrite of compounds 1b, 2b and 9b,

respectively.

4.63. 3-(2-Pyridyl)pyrazolo[5,1-c][1,2,4]benzotriazine-

5-oxide (27a)

From compound 27 at 80–90°C. Red crystals; TLC

eluent ethyl acetate/chloroform 7/3; IR w (cm⁻¹): 1560;

¹H NMR (CDCl₃): l 8.83 (s, 1H, H-2), 8.60 (m, 2H,

H-6 and Py), 8.44 (d, 1H, Py), 8.33 (d, 1H, H-9), 7.97

(t, 1H, H-8), 7.77 (t, 1H, Py), 7.68 (t, 1H, H-7), 7.21 (t,

1H, Py).

4.70. 2-Phenyl-3-carboxypyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (1c)

From compound 1b. Yellow crystals; TLC eluent

toluene/ethyl acetate/acetic acid/ 8/2/1; IR w (cm⁻¹):

1

1720; H NMR (DMSO-d₆): l 8.46 (m, 3H, H-6, H-9

4.64. 3-(2-Pyridyl)-8-chloropyrazolo[5,1-c][1,2,4]benzo-

triazine 5-oxide (28a)

and 2-Ph), 8.14 (m, 2H, H-8, 2-Ph), 7.82–7.70 (m, 3H,

H-7, 2-Ph), 7.52 (m, 1H, 2-Ph).

From compound 28 at 40–50°C. Red crystals; TLC

eluent ethyl acetate/chloroform 7/3; IR w (cm⁻¹): 1560;

¹H NMR (CDCl₃): l 8.85 (s, 1H, H-2), 8.65 (d, 1H,

Py), 8.49 (m, 2H, H-6, H-9), 8.30 (dd, 1H, H-7), 7.80 (t,

1H, Py), 7.60 (d, 1H, Py), 7.22 (t, 1H, Py).

4.71. 2-Phenyl-3-carboxy-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (2c)

From compound 2b. Yellow crystals; TLC eluent

ethyl acetate/chloroform 7/3; IR w (cm⁻¹): 3300–3140,

388

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

1

1690, 1545; H NMR (DMSO-d₆): l 12.90 (s, 1H, OH),

8.48 (m, 2H, H-6, H-9), 7.82 (m, 3H, H-7, 2-Ph), 7.50

(m, 3H, 2-Ph).

NMR (CDCl₃): l 8.46 (d, 1H, H-6), 8.38 (d, 1H, H-9),

7.58 (dd, 1H, H-7), 4.35 (q, 2H, CH₂), 2.70 (s, 3H,

CH₃), 1.35 (t, 3H, CH₃).

4.78. General procedure for the synthesis of 3e, 4f, 5e,

5g, 6e, 7f, 7h, and 10e

4.72.2-Methyl-3-carboxy-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (9c)

Compounds 3a, 4a, 5a, 6a, 7a and 10a (0.21 mmol)

were each dissolved in 15 ml of chloroform to which an

equimolar amount of bromine was slowly added. From

compound 5a (0.21 mmol), an excess of bromine (1

mmol) gave the tetrabromo derivative 5g. From com-

pound 7a a mixture of bromo derivatives 7f and 7h has

always been obtained; they were separated by column

chromatography.

From compound 9b. Yellow crystals; TLC eluent

toluene/ethyl acetate/acetic acid 8/2/1; IR w (cm⁻¹):

3300–3100, 1720, 1560; H NMR (DMSO-d₆): l 12.00

(s, 1H, OH), 8.44 (d, 1H, H-6), 8.36 (d, 1H, H-9), 7.80

(dd, 1H, H-7), 2.62 (s, 3H, CH₃).

1

4.73. General procedure for the synthesis of 1d, 2d, 8d

and 9d

The solution was stirred for 2 h at r.t. After evapora-

tion the residue was recrystallized from the suitable

solvent.

Compounds 1c, 2c, 8a and 9c (100 mg) were added to

thionyl chloride (1.00 ml) and reﬂuxed for 30 min. The

ﬁnal solution was evaporated to dryness and 10 ml of

anhydrous ethanol were added; the reaction was moni-

tored by TLC. The precipitate was ﬁltered and puriﬁed

by recrystallization.

4.79. 2-Phenyl-3-bromo-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (3e)

From compound 3a. Yellow crystals; TLC eluent

1

toluene/ethyl acetate 8/2; IR w (cm⁻¹): 1550; H NMR

(CDCl₃): l 8.45 (m, 2H, H-6, H-9), 8.10 (m, 2H, 2-Ph),

7.55 (m, 4H, H-7, 2-Ph).

4.74. 2-Phenyl-3-ethoxycarbonylpyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (1d)

4.80. 2-(2-Methoxy-5-bromophenyl)-3-bromo-8-chloro-

pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (4f)

From compound 1c. Yellow crystals; TLC eluent

1

toluene/ethyl acetate 8/2; IR w (cm⁻¹): 1720, 1550; H

NMR (CDCl₃): l 8.60 (d, 1H, H-6), 8.51 (d, 1H, H-9),

8.36 (d, 2H, 2-Ph), 8.08 (m, 3H, 2-Ph), 7.79 (m, 2H,

H-7, H-8), 4.40 (q, 2H, CH₂), 1.41(t, 3H, CH₃).

From compound 4a. Yellow crystals; TLC eluent

1

cyclohexane/ethyl acetate 2/1; IR w (cm⁻¹): 1550; H

NMR (DMSO-d₆): l 8.45 (m, 2H, H-6, H-9), 7.78 (m,

2H, H-7, 2-Ph), 7.55 (d, 1H, 2-Ph),7.25 (d, 1H, 2-Ph),

3.85 (s, 3H, CH₃).

4.75. 2-Phenyl-3-ethoxycarbonyl-8-chloropyrazolo-

[5,1-c][1,2,4]benzotriazine 5-oxide (2d)

4.81. 2-(2-Thienyl)-3-bromo-8-chloropyrazolo[5,1-c]-

[1,2,4]benzotriazine 5-oxide (5e)

From compound 2c. Yellow crystals; TLC eluent

ethyl acetate/chloroform 7/3; IR w (cm⁻¹): 1688, 1540,

1105; ¹H NMR (CDCl₃): l 8.50 (m, 2H, H-6, H-9), 7.80

(m, 2H, 2-Ph), 7.55 (m, 4H, H-7, 2-Ph), 4.40 (q, 2H,

CH₂), 1.35 (t, 3H, CH₃).

From compound 5a. Yellow crystals; TLC eluent

1

toluene/ethyl acetate 8/2; IR w (cm⁻¹): 1590; H NMR

(CDCl₃): l 8.48 (d, 1H, H-6), 8.42 (d, 1H, H-9), 8.06 (d,

1H, H-3% thio.), 7.58 (dd, 1H, H-7), 7.51 (d, 1H, H-5%

thio.), 7.21 (t, 1H, H-4% thio.).

4.76. 2-Ethoxycarbonyl-3-phenyl-8-chloropyrazolo-

[5,1-c][1,2,4]benzotriazine 5-oxide (8d)

4.82. 2-(3,4,5-Tribromothien-2-yl)-3-bromo-8-chloro-

pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (5g)

From compound 8a. Yellow crystals; TLC eluent

chloroform/methanol 10/1; IR w (cm⁻¹): 1720, 1560; ¹H

NMR (DMSO-d₆): l 8.48 (m, 2H, H-6, H-9), 7.86 (dd,

1H, H-7), 7.58–7.44 (m, 5H, Ph), 4.35 (q, 2H, CH₂),

1.35 (t, 3H, CH₃).

From compound 5a. Orange crystals; TLC eluent

1

toluene/ethyl acetate 8/2; IR w (cm⁻¹): 1560; H NMR

(CDCl₃): l 8.50 (d, 1H, H-6), 8.39 (d, 1H, H-9), 7.64

(dd, 1H, H-7).

4.77. 2-Methyl-3-ethoxycarbonyl-8-chloropyrazolo-

[5,1-c][1,2,4]benzotriazine 5-oxide (9d)

4.83. 2-(3-Thienyl)-3-bromo-8-chloropyrazolo[5,1-c]-

[1,2,4]benzotriazine 5-oxide (6e)

From compound 9c. Yellow crystals; TLC eluent

chloroform/methanol 10/1; IR w (cm⁻¹): 1690, 1560; ¹H

From compound 6a. Yellow crystals; TLC eluent

1

toluene/ethyl acetate 8/2; IR w (cm⁻¹): 1560; H NMR

G. Guerrini et al. / Il Farmaco 54 (1999) 375–389

389

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(CDCl₃): l 8.48 (d, 1H, H-6), 8.42 (d, 1H, H-9), 8.28

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4.84. 2-(3-Bromofur-2-yl)-3-bromo-8-chloropyrazolo-

[5,1-c][1,2,4]benzotriazine 5-oxide (7f)

From compound 7a. From column chromatography

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Dark yellow crystals; IR w (cm⁻¹): 1560; ¹H NMR

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From compound 7a. From column chromatography

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1

Yellow crystals; IR w (cm⁻¹): 1560; H NMR (CDCl₃):

l 8.48 (m, 2H, H-6 and H-9), 7.55 (dd, 1H, H-7), 6.95

(d, 1H, H-5% fur.), 6.92 (s, 1H, H-3), 6.50 (d, 1H, H-4%

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4.86. 2-Methyl-3-bromo-8-chloropyrazolo[5,1-c][1,2,4]-

benzotriazine 5-oxide (10e)

From compound 10a. Yellow crystals; TLC eluent

1

toluene/ethyl acetate 8/2; IR w (cm⁻¹): 1590; H NMR

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Article Doi

Benzodiazepine receptor ligands III. Synthesis and biological evaluation of 2- and/or 3-substituted pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides

DOI: 10.1016/S0014-827X(99)00044-0

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Article abstract of DOI:10.1016/S0014-827X(99)00044-0

Full text of DOI:10.1016/S0014-827X(99)00044-0

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