New cycloalkylpyrazoles as potential cyclooxygenase inhibitors

Article abstract of DOI:10.1016/S0014-827X(98)00090-1

In this study some cycloalkyl-3-(N-substituted carbamoyl)-1-phenylpyrazoles have been synthesized in order to screen their capability to inhibit human cyclooxygenase. The synthetic pathway is based on the well known property of nitrilimines to undergo 1,3-dipolar cycloaddition reactions. The structures of all the synthesized compounds have been elucidated by means of both analytical and spectroscopic methods.

Full text of DOI:10.1016/S0014-827X(98)00090-1

Il Farmaco 53 (1998) 698–708
New cycloalkylpyrazoles as potential cyclooxygenase inhibitorsꢀ
M.C. Cardia *, L. Corda, A.M. Fadda, A.M. Maccioni, E. Maccioni, A. Plumitallo
Department Farmaco Chimico Tecnologico, Via Ospedale 72, I-09124 Cagliari, Italy
Abstract
In this study some cycloalkyl-3-(N-substituted carbamoyl)-1-phenylpyrazoles have been synthesized in order to screen their
capability to inhibit human cyclooxygenase. The synthetic pathway is based on the well known property of nitrilimines to undergo
1,3-dipolar cycloaddition reactions. The structures of all the synthesized compounds have been elucidated by means of both
analytical and spectroscopic methods. © 1998 Elsevier Science S.A. All rights reserved.
Keywords: Cycloalkyl-3-(N-substituted carbamoyl)-1-phenylpyrazoles; Analgesic and antipyretic activity
Several derivatives of pyrazole are of pharmaceutical
interest due to their analgesic power. Among them,
derivatives of 5-isopyrazolone and pyrazolidine-3,5-
dione are worth noting due to their clinical interest.
Moreover, the synthesis and biological activity of some
3-substituted-1-phenylpyrazoles have been reported. It
was also observed that pyrazoles bearing an electron
donating group in the 5-position of the heterocycle ring
showed the highest analgesic and anti-inflammatory
activity. This was particularly evident when the sub-
stituent in the 3-position were either N-substituted-
aminomethyl or -carbamoyl groups [1]. Other
substituents, both on the benzene and on the hetero-
cyclic ring, can severely modify the biological properties
of such molecules [2,3].
In the present paper, we report on the synthesis of
some 3-(N-substituted)-carbamoyl-1-phenylpyrazoles.
The synthesized compounds are shown in Fig. 1. The
synthetic pathway to compounds 8–22 is depicted in
Schemes 1 and 2.
Chlorophenylhydrazones (1) were synthesized slightly
modifying literature methods [4], i.e. by reacting the
diazonium salt of the appropriate amine with 2-
chloroacetoacetate.
As expected, nitrilimines show two different reacting
pathways: 1,3-dipolar cycloaddition and 1,3-electro-
philic addition.
Two different products can be obtained and their
formation and ratio depend on several factors, mainly
on the kind of the dipolarophile and the experimental
conditions. Significative amounts of the 1,3-addition
products 5 are formed in the presence of weak
dipolarophiles.
Even if the enamine acts as a good polarophile, two
distinct reaction pathways have been observed using
dry chloroform as the solvent. When employing dry
benzene a moderate increase of the cycloaddition
product was observed.
The electrophilic attack of the chlorophenylhydra-
zone undergo both on the cycloalkane carbon and on
the heterocyclic nitrogen atom, leading to the forma-
tion of either the cycloaddition product 4 or the 1,3-
electrophilic addition product 5, respectively.
As shown by TLC, compound 5 consists of two very
1
similar products which were characterized by H NMR
as the E- and Z-diastereoisomers (Fig. 2).
1H NMR showed a small chemical shift (1.5 ppm)
between the imine protons of the E- and Z-
diastereoisomers. This behavior is in contrast to what
has been observed for analogous compounds where the
chemical shift is in the range of 4–5 ppm [11–13]. This
is probably due to the fact that both the E- and
Z-diastereoisomers undergo the formation of intra-
molecular hydrogen bonds, that leads to the formation
of a six- and five-membered ring, respectively.
The synthesis of 1-phenyl-3-carbethoxycycloalkyl-
pyrazoles (4) (Scheme 1) has been based on the well
known capability of nitrilimines (1) to undergo 1,3-
dipolar cycloadditions in the presence of dipolarophiles
[4–10].
ꢀ Dedicated to Professor Antonio Maccioni.
* Corresponding author.
0014-827X/98/$ - see front matter © 1998 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(98)00090-1

M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
699
Fig. 1. Structures of the compounds under investigation.
Evidence of this is also given by differences in the
physical properties of the two compounds. It is well
known that the formation of intramolecular hydrogen
bonds, rather than intermolecular, can dramatically
affect the physical properties of compounds. In the
case of the E-diastereoisomer, the hydrogen bond is
formed between the imine hydrogen and the carbonyl
oxygen, giving rise to a six-membered ring, while for
the Z-isomer it is formed between the imine hydrogen
and a nitrogen atom, leading to the formation of a
less stable five-membered ring (Fig. 3). This is proba-
bly due to the lower stability of the intramolecular
hydrogen bond and, in the case of the Z-diastereoiso-
mer, a higher number of intermolecular bonds are
formed, enhancing the cohesion between the
molecules. All the Z-derivatives showed melting
points about 20–40°C higher than the corresponding
E-diastereoisomers.

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M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
Scheme 1. Synthetic pathway to compound 4. a, R=3-NO2, n=2; a%, R=3-NO2, n=1; b, R=3-CF3, n=2; c, R=4-Cl, n=2; d, R=4-F, n=2;
e, R=4-CH3, n=2.
Scheme 2. Synthetic pathway to compounds 8–22. 8: R=3-NO2, NR%R%%=morpholino; 9: R=3-NO2, NR%R%%=pyrrolidino; 10: R=3-NO2,
NR%R%%=N-methylpiperazine; 11: R=3-CF3, NR%R%%=morpholino; 12: R=3-CF3, NR%R%%=pyrrolidino; 13: R=3-CF3, NR%R%%=N-
methylpiperazino; 14: R=4-F, NR%R%%=morpholino; 15: R=4-F, NR%R%%=pyrrolidino; 16: R=4-F, NR%R%%=N-methylpiperazine; 17: R=4-
Cl, NR%R%%=morpholino; 18: R=4-Cl, NR%R%%=pyrrolidino; 19: R=4-Cl, NR%R%%=N-methylpiperazine; 20: R=4-CH3, NR%R%%=morpholino;
21: R=4-CH3, NR%R%%=pyrrolidino; 22: R=4-CH3, NR%R%%=N-methylpiperazine.

M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
701
Fig. 2. 1H NMR spectra for (a) Z- and (b) E-diastereoisomers of compounds 5.
Only in the reaction between the cyclopentanone
enamine (compound 2; n=1) and the chlorophenylhy-
drazones (1) four compounds were isolated. The pyra-
compound, which can be converted into the pyra-
zole derivative 4, through the loss of a morpholine
molecule, by simple heating in acetic acid for a few
minutes.
zolidinic derivative
3 was separated as a pure

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M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
acetate [16] were prepared according to established
procedures. The chlorophenylhydrazones (1) were pre-
pared as described in literature [2,4,17,18]: 0.2 mol of the
diazonium salt of the corresponding amide were added
to a cool mixture of 0.2 mol of sodium acetate and 0.2
mol of 2-chloroacetoacetate in 300 ml of ethanol. The
mixture was then stirred for 3 h and left overnight at
0°C. The precipitated product was filtered off, washed
with water and recrystallized from the suitable solvent.
1.2. Synthesis of 1-(3-nitrophenyl)-3-carbethoxy-
4,5,6,7-tetrahydroindazole (4a) (general method)
Fig. 3. E- and Z-diastereoisomers of compounds 5.
In a three necked flask 6.7 g (0.04 mol) of freshly
distilled enamine (2) and 4.1 g (0.04 mol) of dry triethyl-
amine were dissolved in 50 ml of dry chloroform. A
solution of phenylhydrazone (1), 10.84 g (0.04 mol),
dissolved in 100 ml of dry chloroform was added
dropwise at room temperature (r.t.). The reaction mix-
ture was stirred at r.t. for 12 h and then washed three
times with water. The organic layer was dried on dry
sodium sulfate. Evaporation of the solvent under re-
duced pressure yielded a thick oil which was purified by
column chromatography, with a chloroform–hexane
(1:1) mixture used as the eluent.
Column chromatography yielded two products. The
former is the expected 1-(3-nitrophenyl)-3-carbethoxy-
4,5,6,7-tetrahydroindazole, which was friabilized with
isopropyl ether–hexane and then crystallized from
ethanol. Pale yellow crystals; m.p. 120–121°C. Yield
37%.
The reaction pathway is likely the same when the
cyclohexanone enamines are used; four compounds are
obtained as shown by TLC. Unfortunately, although the
pyrazolidinic derivative is likely evidenced by chro-
matography, any attempt to isolate it failed. However,
TLC of the reaction crude, as well as in the case of
cyclopentanone enamines, showed the presence of a
compound which can be easily converted into the pyra-
zolic derivative by simple heating in acetic acid.
Carboxylic acids (6) were obtained by hydrolysis of
the corresponding esters and were then converted into
acid chlorides (7) by treatment with thionyl chloride.
Condensation of acid chlorides (7) with the appropri-
ate amines yielded the amides (8–22). These products
were also obtained by direct coupling of carboxylic acids
(6) with the appropriate amines in the presence of
dicyclohexyl carbodiimide (DCC).
IR spectra of compounds 4: all the synthesized com-
pounds 4 show a well detectable CꢀO adsorption band
1. Experimental
between 1710 and 1720 cm−1
.
1H NMR (CDCl3): l 1.36 (t, 3H, CH3); 1.78 (t, 4H,
CH2); 2.79 (t, 2H, CH2); 2.85 (t, 2H, CH2); 4.40 (q, 2H,
O–CH2); 7.60–8.40 (m, 4H, Ar).
TLC analysis of the latter revealed the presence of two
products with very similar Rf values that were isolated
by crystallization.
All melting points were determined using an elec-
trothermal melting point apparatus and are uncorrected.
The IR spectra were obtained in Nujol with a Perkin–
1
Elmer 398 spectrophotometer; H NMR spectra were
measured on a Varian EM 360 L using deuterochloro-
form as solvent and TMS as internal standard. Chemical
shifts were reported as l (ppm). Microanalysis for CHN
were carried out on a Carlo Erba 1106 analyser. Electron
ionization (EI) mass spectra were obtained by a Fisons
QMD 1000 mass spectrometer (70 eV, 200 mA, ion
source temperature 200°C). The samples were intro-
duced directly into the ion source. Found molecular ions
were in agreement with theoretical values. TLC was
performed on silica gel plates (Merck F 254). Chro-
matography was accomplished with Merck silica gel
(70–230 mesh).
Analytical and spectral data are in agreement with
structure 5 (Scheme 1).
IR spectra of compounds 5: all the synthesized com-
pounds 5 show a well-detectable CꢀO adsorption band
ranging between 1710 and 1720 cm−1 and a clear
stretching N–H band at 3300–3450 cm−1
.
1H NMR spectra (Fig. 2) show the presence of the two
diastereoisomers 5a-E and 5a-Z; m.p.: 79.5–80.5 and
124–126°C, respectively.
1.2.1. 2-(N-Morpholino)-2-(3-nitrophenyl)-hydrazidoyl-
oxalic ethyl ester (5a-E)
1.1. Starting materials
1H NMR (CDCl3): l 1.39 (t, 3H, CH3); 3.05 (t, 4H,
CH2–N); 3.85 (t, 4H, O–CH2); 4.34 (q, 2H, O–CH2);
7.41–7.96 (m, 4H, Ar); 10.56 (s, 1H, NH).
1-N-Morpholinocyclohex-1-ene (2), 1-N-morpholino-
cyclopent-1-ene (2) (n=1) [14,15], and 2-chloroaceto-

M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
703
Table 1
1-Aryl-3-carbethoxy-cycloalkylpyrazole (4)
Comp.
R
n
Formula
M+ M.p. (°C)
Crystal/solvent
Yield (%)
C (%)a
H (%)a
N (%)a
4a
4a%
4b
4c
4d
4e
m-NO2
m-NO2
m-CF3
p-Cl
p-F
p-CH3
2
1
2
2
2
2
C16H17N3O4
C15H15N3O4
C17H17N2O2F3
C16H17N2O2Cl
C16H17N2O2F
C17H20N2O2
315
301
338
304
288
284
120–121
127–128
118–119
143
132–133
110–111
Ethanol
Ethyl/ac.
Ethanol
Ethanol
Ethanol
Ethanol
37
32
35
64
53
67
60.95 (61.25)
59.79 (60.05)
60.35 (60.21)
63.06 (62.92)
66.66 (66.87)
71.80 (72.04)
5.43 (5.47)
5.02 (5.05)
5.07 (5.05)
5.62 (5.65)
5.94 (5.91)
7.09 (7.11)
13.32 (13.28)
13.95 (14.00)
8.28 (8.33)
9.19 (9.12)
9.71 (9.67)
9.85 (9.81)
a Found values in parentheses.
1.2.2. 2-(N-Morpholino)-2-(3-nitrophenyl)-hydrazidoyl-
oxalic ethylester (5a-Z)
1.2.5. 2-(N-Morpholino)-2-(3-trifluoromethylphenyl)-
hydrazidoyl-oxalic ethyl ester (5b-E)
1H NMR (CDCl3): l 1.39 (t, 3H, CH3); 3.05 (t, 4H,
CH2–N); 3.85 (t, 4H, O–CH2); 4.34 (q, 2H, O–CH2);
7.41–7.96 (m, 4H, Ar); 9.12 (s, 1H, NH).
1H NMR (CDCl3): l 1.38 (t, 3H, CH3); 3.04 (t, 4H,
CH2–N); 3.83 (t, 4H, O–CH2); 4.30 (q, 2H, O–CH2);
7.25–7.41 (m, 4H, Ar); 10.60 (s, 1H, NH).
The same method has been employed for the synthe-
sis of the following products listed in Table 1.
1.2.6. 2-(N-Morpholino)-2-(3-trifluoromethylphenyl)-
hydrazidoyl-oxalic ethyl ester (5b-Z)
1H NMR (CDCl3): l 1.38 (t, 3H, CH3); 3.04 (t, 4H,
CH2–N); 3.83 (t, 4H, O–CH2); 4.30 (q, 2H, O–CH2);
7.25–7.41 (m, 4H, Ar); 9.08 (s, 1H, NH).
1.2.3. 1-(3-Nitrophenyl)-3-carbethoxy-6H-4,5-
dihydroindazole (4a%) (n=1)
Column chromatography of the reaction crude
yielded three products:
1. pale yellow crystals, compound 4a% (n =1), m.p.
1.2.7. 1-(4-Chlorophenyl)-3-carbethoxy-4,5,6,7-
tetrahydroindazole (4c)
1
127–128°C. Yield 32%. H NMR (CDCl3): l 1.36
(t, 3H, CH3); 1.78–1.83 (m, 2H, CH2); 2.79 (t, 2H,
CH2); 2.85 (t, 2H, CH2); 4.40 (q, 2H, CH2); 7.60–
8.40 (m, 4H, Ar);
Column chromatography of the reaction crude, ob-
tained as described above, yielded two products. Com-
pound 5 (E and Z) was obtained in lower yield than in
the previously described reactions, while the yield of
compound 4c was enhanced. Crystallization from
ethanol yielded compound 4c as white crystals, m.p.
143°C. Yield 64%.
2. 5-E and 5-Z diastereoisomers;
3. the third product is the 1-(3-nitrophenyl)-4aH-3-
carbethoxy-8a-morpholino-5,6,7,8a-tetrahydroinda-
zole (3a) (n=1).
1H NMR (CDCl3): l 1.36 (s, 3H, CH3); 1.50–1.57
(m, 2H, CH2); 1.76 (q, 2H, CH2); 1.81 (t, 2H, CH2);
1.89 (t, 1H, CH); 2.70 (t, 4H, N–CH2); 3.69 (t, 4H,
O–CH2); 4.40 (q, 2H, O–CH2); 7.60–8.40 (m, 4H, Ar).
These compounds 3 have only been isolated when the
cyclopentanone enamines are employed. Their structure
1H NMR (CDCl3): l 1.42 (t, 3H, CH3); 1.80 (t, 4H,
CH2); 2.66 (t, 2H, CH2); 2.81 (t, 2H, CH2), 4.42 (q, 2H,
O–CH2); 7.20–7.50 (m, 4H, Ar).
1.2.8. 2-(N-Morpholino)-2-(4-chlorophenyl)-
hydrazidoyl-oxalic ethyl ester (5c-E)
1
was determined by means of H NMR and mass spec-
M.p. 86–87°C. 1H NMR (CDCl3): l 1.36 (t, 3H,
CH3); 3.08 (t, 4H, CH2–N); 3.81 (t, 4H, O–CH2); 4.34
(q, 2H, O–CH2); 7.10–7.27 (m, 4H, Ar); 10.62 (s, 1H,
NH).
troscopy. By heating, during the crystallization process,
compound 3 is converted into 4a% (n=1). The reaction
is highly favored by acids. As an example, the conver-
sion is completed in a few minutes in the presence of
acetic acid.
1.2.9. 2-(N-Morpholino)-2-(4-chlorophenyl)-
hydrazidoyl-oxalic ethylester (5c-Z)
1.2.4. 1-(3-Trifluoromethylphenyl)-3-carbethoxy-
4,5,6,7-tetrahydroindazole (4b)
The pyrazole derivative 4b was obtained as pale
yellow crystals, m.p. 118–119°C. Yield 35%.
1H NMR (CDCl3): l 1.35 (t, 3H, CH3); 1.79 (t, 4H,
CH2); 2.78 (t, 2H, CH2); 2.85 (t, 2H, CH2), 4.32 (q, 2H,
O–CH2); 7.80–8.40 (m, 4H, Ar).
Along with the expected cycloaddition product 4b,
the electrophilic addition product 5b (E and Z) was
also obtained, m.p. 83–85 and 110–111°C, respectively.
1
M.p. 112–113°C. H NMR (CDCl3): l 1.36 (t, 3H,
CH3); 3.08 (t, 4H, CH2–N); 3.81 (t, 4H, O–CH2); 4.34
(q, 2H, O–CH2); 7.10–7.27 (m, 4H, Ar); 9.01 (s, 1H,
NH).
1.2.10. 1-(4-Fluorophenyl)-3-carbethoxy-4,5,6,7-
tetrahydroindazole (4d)
Compound 4d was obtained as previously described.
White crystals, m.p. 132–133°C. Yield 53%.

704
M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
Table 2
1-Aryl-4,5,6,7-tetrahydroindazole-3-carboxylic acid (6)
Comp.
R
n
Formula
M+ M.p. (°C) Crystal/solvent
Yield (%) C (%)a
H (%)a
N (%)a
6a
6a%
6b
6c
6d
6e
m-NO2
m-NO2
m-CF3
p-Cl
p-F
p-CH3
2
1
2
2
2
2
C14H13N3O4
C13H11N304
C15H13N2O2F3 310 209–210
C14H13N2O2Cl
C14H13N2O2F
C15H16N2O2
287 203
273 206–207
AcOH/AcOEt
AcOH/acetonitrile 65
AcOH dil.
AcOH dil.
AcOH dil.
AcOH dil.
68
58.53 (58.72) 4.56 (4.59) 14.63 (14.55)
57.14 (56.95) 4.06 (4.08) 15.38 (15.29)
66
85
78
90
58.07 (57.86) 4.22 (4.19)
9.02 (8.97)
276 217
260 213–214
256 199–200
60.77 (60.90) 4.73 (4.70) 10.12 (10.08)
64.61 (64.51) 5.03 (4.99) 10.76 (10.70)
70.29 (70.51) 6.29 (6.31) 10.93 (10.89)
a Found values in parentheses.
1H NMR (CDCl3): l 1.43 (t, 3H, CH3); 1.81 (t, 4H,
CH2); 2.67 (t, 2H, CH2); 2.82 (t, 2H, CH2), 4.42 (q, 2H,
O–CH2); 7.30–7.60 (m, 4H, Ar).
1.3. Synthesis of 1-aryl-4,5,6,7-tetrahydroindazole-3-
carboxylic acid (6) (general method)
Also in this case the electrophilic cycloaddition prod-
ucts 5d (E and Z) diastereoisomers were obtained, m.p.
78–79 and 108–110°C, respectively.
The carboxylic acids 6 (Table 2) were obtained by
hydrolysis of the corresponding esters 4.
The hydrolysis was accomplished following two dif-
ferent methods:
1.2.11. 2-(N-Morpholino)-2-(4-fluorophenyl)-
hydrazidoyl-oxalic ethyl ester (5d-E)
1.3.1. 1-(3-Nitrophenyl)-4,5,6,7-tetrahydroindazole-3-
carboxylic acid (6a) (method a)
1H NMR (CDCl3): l 1.37 (t, 3H, CH3); 3.05 (t, 4H,
CH2–N); 3.81 (t, 4H, O–CH2); 4.35 (q, 2H, O–CH2);
6.95–6.97 (m, 4H, Ar); 10.64 (s, 1H, NH).
To a solution of KOH (14 g) in H2O (70 ml) and
methanol (70 ml) the ester 4a (31.5 g, 0.1 mol) was
added and the mixture was refluxed for 4 h, then
allowed to cool down to r.t., diluted with water (200
ml) and finally neutralized with 10% HCl water solu-
tion. The obtained solid was filtered and crystallized
from acetic acid–ethyl acetate.
1.2.12. 2-(N-Morpholino)-2-(4-fluorophenyl)-
hydrazidoyl-oxalic ethyl ester (5d-Z)
1H NMR (CDCl3): l 1.37 (t, 3H, CH3); 3.05 (t, 4H,
CH2–N); 3.81 (t, 4H, O–CH2); 4.35 (q, 2H, O–CH2);
6.95–6.97 (m, 4H, Ar); 9.02 (s, 1H, NH).
1.3.2. 1-(3-Nitrophenyl)-4,5,6,7-tetrahydroindazole-3-
carboxylic acid (6a) (method b)
The ester 4a (0.014 mol) was dissolved in 25 ml of
boiling ethanol and 25 ml of water and then 5 ml of a
water solution of 30% NaOH was added.
1.2.13. 1-(4-Methylphenyl)-3-carbethoxy-4,5,6,7-
tetrahydroindazole (4e)
The previously reported procedure was employed for
the synthesis of compound 4e.
1H NMR (CDCl3): l 1.40 (t, 3H, CH3); 1.80 (t, 4H,
CH2); 2.28 (s, 3H, CH3); 2.63 (t, 2H, CH2); 2.70 (t, 2H,
CH2), 4.39 (q, 2H, O–CH2); 7.40–7.70 (m, 4H, Ar).
Together with the expected compound 4e the corre-
sponding electrophilic addition compounds 5e (E and
Z) have been obtained, m.p. 73–74 and 98–99°C,
respectively.
The reaction mixture was refluxed and the ethanol
was distilled off, during which time the volume was
kept constant by adding water.
The mixture was then cooled and neutralized with
10% HCl water solution. The solution was then
refluxed for a few minutes in the presence of charcoal
and rapidly filtered. To the boiling solution HCl
was added and the acid 6a precipitated out of this
solution.
The carboxylic acid 6a was obtained as white crystals
that were further purified by crystallization from acetic
acid–ethyl acetate. Yield is generally higher following
method b.
1.2.14. 2-(N-Morpholino)-2-(4-methylphenyl)-
hydrazidoyl-oxalic ethyl ester (5e-E)
1H NMR (CDCl3): l 1.39 (t, 3H, CH3); 2.88 (s, 3H,
Ar–CH3); 3.07 (t, 4H, CH2–N); 3.83 (t, 4H, O–CH2);
4.31 (q, 2H, O–CH2); 6.95–7.26 (m, 4H, Ar); 10.70 (s,
1H, NH).
Pale yellow crystals, m.p. 203°C. Yield 68%.
IR spectra: all the synthesized acids 6 show the CꢀO
adsorption band ranging between 1700 and 1710 cm−1
and a large band corresponding to the OH group from
1.2.15. 2-(N-Morpholino)-2-(4-methylphenyl)-
hydrazidoyl-oxalic ethyl ester (5e-Z)
1H NMR (CDCl3): l 1.39 (t, 3H, CH3); 2.88 (s, 3H,
Ar–CH3); 3.07 (t, 4H, CH2–N); 3.83 (t, 4H, O–CH2);
4.31 (q, 2H, O–CH2); 6.95–7.26 (m, 4H, Ar); 9.04 (s,
1H, NH).
3000 to 2800 cm−1
.
1H NMR (CDCl3): l 1.84 (t, 4H, CH2); 2.80 (t, 2H,
CH2); 2.86 (t, 2H, CH2); 5.30 (s, 1H, COOH); 7.60–
8.40 (m, 4H, Ar).

M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
705
The carboxylic acids listed in Table 2 were prepared
according to method b.
1.4. Synthesis of 1-aryl-3-chlorocarbonyl-4,5,6,7-
tetrahydroindazole (7) (general method)
1.3.3. 1-(3-Nitrophenyl)-4,5-dihydro-6H-cyclopenta-
[b]-pyrazole-3-carboxylic acid (6a%) (n=1).
Compound 6a% was synthesized as described above.
Pale yellow crystals were obtained, m.p. 206–207°C.
Yield 65%.
1.4.1. 1-(3-Nitrophenyl)-3-chlorocarbonyl-4,5,6,7-
tetrahydroindazole (7a)
To a solution of the carboxylic acid (6a) 2.87 g (0.01
mol) in dry benzene (30 ml), thionyl chloride 1.5 ml
(0.02 mol) was added dropwise under vigorous stirring.
The mixture was refluxed for 1 h and then the solvent
was removed under reduced pressure. The acid was
obtained as white powder that was crystallized from
ethanol. Yield 52%, m.p. 107–108°C.
1H NMR (CDCl3): l 1.78–1.83 (m, 2H, CH2); 2.80
(t, 2H, CH2); 2.86 (t, 2H, CH2); 5.30 (s, 1H, COOH);
7.60–8.40 (m, 4H, Ar).
1.3.4. 1-(3-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-
indazole-3-carboxylic acid (6b)
White crystals, m.p. 209–210°C. Yield 66%.
1H NMR (CDCl3): l 1.85 (t, 4H, CH2); 2.76 (t, 2H,
CH2); 2.80 (t, 2H, CH2); 5.29 (s, 1H, COOH); 7.50–
8.30 (m, 4H, Ar).
IR spectra: all the prepared acid chlorides show a
clear CꢀO stretching band at 1780–1800 cm−1
.
1H NMR (CDCl3): l 1.80 (t, 4H, CH2); 3.68 (t, 2H,
CH2); 3.94 (t, 2H, CH2); 7.58–8.32 (m, 4H, Ar).
The acid chlorides (Table 3) were obtained according
to this method.
1.3.5. 1-(4-Chlorophenyl)-4,5,6,7-tetrahydroindazole-3-
carboxylic acid (6c)
White crystals, m.p. 217°C. Yield 85%.
1H NMR (CDCl3): l 2.44 (t, 4H, CH2); 3.23 (t, 2H,
CH2); 3.44 (t, 2H, CH2); 5.25 (s, 1H, COOH); 7.40–
7.80 (m, 4H, Ar).
1.4.2. 1-(3-Nitrophenyl)-3-chlorocarbonyl-6H-4,5-
dihydroindazole (7a%) (n=1)
1H NMR (CDCl3): l 1.79–1.81 (m, 2H, CH2); 3.68
(t, 2H, CH2); 3.94 (t, 2H, CH2); 7.58–8.32 (m, 4H, Ar).
1.4.3. 1-(3-Trifluoromethylphenyl)-3-chlorocarbonyl-
4,5,6,7-tetrahydroindazole (7b)
1.3.6. 1-(4-Fluorophenyl)-4,5,6,7-tetrahydroindazole-3-
carboxylic acid (6d)
White crystals, m.p. 213–214°C. Yield 78%.
1H NMR (CDCl3): l 2.42 (t, 4H, CH2); 3.25 (t, 2H,
CH2); 3.47 (t, 2H, CH2); 5.26 (s, 1H, COOH); 7.40–
7.90 (m, 4H, Ar).
1H NMR (CDCl3): l 1.79 (t, 4H, CH2); 3.62 (t, 2H,
CH2); 3.88 (t, 2H, CH2); 7.56–8.29 (m, 4H, Ar).
1.4.4. 1-(4-Chlorophenyl)-3-chlorocarbonyl-4,5,6,7-
tetrahydroindazole (7c)
1H NMR (CDCl3): l 1.80 (t, 4H, CH2); 2.67 (t, 2H,
CH2); 2.76 (t, 2H, CH2); 7.33–7.50 (m, 4H, Ar).
1.3.7. 1-(4-Methylphenyl)-4,5,6,7-tetrahydroindazole-3-
carboxylic acid (6e)
White crystals, m.p. 199–200°C. Yield 90%.
1H NMR (CDCl3): l 2.18 (t, 4H, CH2); 2.37 (s, 3H,
CH3); 2.45 (t, 2H, CH2); 2.50 (t, 2H, CH2); 5.00 (s, 1H,
COOH); 7.40–8.60 (m, 4H, Ar).
1.4.5. 1-(4-Fluorophenyl)-3-chlorocarbonyl-4,5,6,7-
tetrahydroindazole (7d)
1H NMR (CDCl3): l 1.82 (t, 4H, CH2); 2.55 (t, 2H,
CH2); 2.64 (t, 2H, CH2); 7.50–8.31 (m, 4H, Ar).
Table 3
1-Aryl-3-chlorocarbonyl-4,5,6,7-tetrahydroindazole (7)
Comp.
R
n
Formula
M+ M.p. (°C)
Crystal/solvent
Yield (%)
C (%)a
H (%)a
N (%)a
7a
7a%
7b
7c
m-NO2
m-NO2
m-CF3
p-Cl
2
1
2
2
C14H12N3O3Cl
C13H10N3O3Cl
C15H12N2OF3Cl
C14H12N2OCl2
305
291
328
295
107–108
110–111
105–106
111–112
Ethanol
Ethanol
Ethanol
Ethanol/
n-hexane
Ethanol/
n-hexane
Ethanol
52
50
47
80
55.00 (55.28)
53.53 (53.70)
54.81 (55.00)
56.97 (56.80)
3.96 (4.00)
3.46 (3.49)
3.68 (3.71)
4.10 (3.98)
13.74 (13.66)
14.40 (14.29)
8.52 (8.47)
9.49 (9.54)
7d
7e
p-F
2
2
C14H12N2OFCl
C15H15N2OCl
278
274
103–104
97–98
75
96
60.33 (60.55)
65.57 (65.38)
4.34 (4.37)
5.50 (5.47)
10.05 (9.98)
10.20 (10.16)
p-CH3
a Found values in parentheses.

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M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
1.4.6. 1-(4-Methylphenyl)-3-chlorocarbonyl-4,5,6,7-
tetrahydroindazole (7e)
1H NMR (CDCl3): l 1.81 (t, 4H, CH2); 2.20 (s,
3H, CH3); 2.25 (t, 2H, CH2); 2.45 (t, 2H, CH2);
7.60–8.40 (m, 4H, Ar).
1.5. Synthesis of 1-aryl-3-(carbamoyl-N-substituted)-
tetrahydroindazoles (8–22) (general method)
Two different methods have been employed for the
synthesis of these compounds.
1.5.1. 1-(3-Nitrophenyl)-3-(morpholinocarbamoyl)-
4,5,6,7-tetrahydroindazole (8) (method a)
To a solution of morpholine 1.2 ml (10 mmol) and
pyridine 0.6 ml (5 mmol) in dry benzene (10 ml) a
solution of the acid chloride 7a (5 mmol) in dry ben-
zene (40 ml) was added dropwise under vigorous stir-
ring. The reaction was stirred for 6 h at r.t., then
water (0.5 ml) was added and the mixture was stirred
for another 15 min. The mixture was extracted with
chloroform and the organic layer washed with 10%
HCl water solution, in order to remove the excess of
pyridine, then with water and finally dried with
sodium sulfate.
Evaporation of the solvent under reduced pressure
yielded an oil that can be easily friabilized with either
n-hexane or isopropyl ether. Yield 80%.
1.5.2. 1-(3-Nitrophenyl)-3-(morpholinocarbamoyl)-
4,5,6,7-tetrahydroindazole (8) (method b)
A mixture of the carboxylic acid (6a) 2.87 g (0.01
mol) and dicyclohexylcarbodiimide (4), 12 g (0.02
mol) in 30 ml dichloromethane and 20 ml of
dimethylformamide was stirred for 15 min at r.t. The
formation of a precipitate of dicyclohexylurea was
observed. An excess of morpholine, 3 ml (0.03 mol),
was then added. The reaction was stirred at r.t. for
30 min then heated up to 60°C and stirred for a
further 8 h.
Filtration of the reaction mixture yielded a white
solid (m.p. 232–233°C), that was identified as dicyclo-
hexylurea. The solution was washed twice with acidic
water (2×10 ml), then with a 10% water solution of
sodium hydrogen carbonate (2×10 ml) and finally
with water.
The organic layer was dried on anhydrous sodium
sulfate and then evaporated under reduced pressure.
An oil was obtained that can be friabilized from iso-
propyl ether and crystallized from ethanol. Yield
65%.
IR spectra: all the synthesized amides show a well
detectable CꢀO band between 1670 and 1640 cm−1
.
1H NMR (CDCl3): l 1.80 (t, 4H, CH2); 2.75 (t,
4H, N–CH2); 3.68 (t, 2H, CH2); 3.75 (t, 4H, O–
CH2); 3.94 (t, 2H, CH2); 7.60–8.32 (m, 4H, Ar).

M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
707
According to this method the following products
(Table 4) were prepared:
1.13. 1-(4-Chlorophenyl)-3-(4%-N-methylpiperazino-
carbamoyl)-4,5,6,7-tetrahydroindazole (16)
1H NMR (CDCl3): l 1.24 (s, 3H, CH3); 1.79 (t, 4H,
CH2); 2.71 (t, 2H, CH2); 2.84 (t, 2H, CH2); 3.74 (t, 4H,
CH2–N–Me); 4.00 (t, 4H, N–CH2); 7.20–7.50 (m, 4H,
Ar).
1.6. 1-(3-Nitrophenyl)-3-(pyrrolidinocarbamoyl)-
4,5,6,7-tetrahydroindazole (9)
1H NMR (CDCl3): l 1.78 (t, 4H, CH2); 1.92 (t, 4H,
CH2); 2.69 (t, 2H, CH2); 2.83 (t, 2H, CH2); 3.64 (t, 4H,
N–CH2); 7.60–8.32 (m, 4H, Ar).
1.14. 1-(4-Fluorophenyl)-3-(morpholinocarbamoyl)-
4,5,6,7-tetrahydroindazole (17)
1.7. 1-(3-Nitrophenyl)-3-(4%-N-methylpiperazinocarba-
moyl)-4,5,6,7-tetrahydroindazole (10)
1H NMR (CDCl3): l 1.77 (t, 4H, CH2); 2.70 (t, 4H,
N–CH2); 3.67 (t, 2H, CH2); 3.75 (t, 4H, O–CH2); 3.97
(t, 2H, CH2); 7.20–7.80 (m, 4H, Ar).
1H NMR (CDCl3): l 1.24 (s, 3H, CH3); 1.79 (t, 4H,
CH2); 2.71 (t, 2H, CH2); 2.84 (t, 2H, CH2); 3.74 (t, 4H,
CH2–N–Me); 4.00 (t, 4H, N–CH2); 7.60–8.32 (m, 4H,
Ar).
1.15. 1-(4-Fluorophenyl)-3-(pyrrolidinocarbamoyl)-
4,5,6,7-tetrahydroindazole (18)
1.8. 1-(3-Trifluoromethylphenyl)-3-(morpholino-
carbamoyl)-4,5,6,7-tetrahydroindazole (11)
1H NMR (CDCl3): l 1.77 (t, 4H, CH2); 1.92 (t, 4H,
CH2); 2.70 (t, 4H, N–CH2); 2.84 (t, 2H, CH2); 3.67 (t,
2H, CH2); 7.20–7.80 (m, 4H, Ar).
1H NMR (CDCl3): l 1.81 (t, 4H, CH2); 2.77 (t, 4H,
N–CH2); 3.70 (t, 2H, CH2); 3.76 (t, 4H, O–CH2); 3.95
(t, 2H, CH2); 7.58–8.28 (m, 4H, Ar).
1.16. 1-(4-Fluorophenyl)-3-(4%-N-methylpiperazino-
carbamoyl)-4,5,6,7-tetrahydroindazole (19)
1.9. 1-(3-Trifluoromethylphenyl)-3-(pyrrolidinocarba-
moyl)-4,5,6,7-tetrahydroindazole (12)
1H NMR (CDCl3): l 1.24 (s, 3H, CH3); 1.77 (t, 4H,
CH2); 2.70 (t, 2H, CH2); 2.84 (t, 2H, CH2); 3.74 (t, 4H,
CH2–N–Me); 4.00 (t, 4H, N–CH2); 7.20–7.80 (m, 4H,
Ar).
1H NMR (CDCl3): l 1.80 (t, 4H, CH2); 1.93 (t, 4H,
CH2); 2.70 (t, 2H, CH2); 2.83 (t, 2H, CH2); 3.64 (t, 4H,
N–CH2); 7.58–8.28 (m, 4H, Ar).
1.10. 1-(3-Trifluoromethylphenyl)-3-(4%-N-methyl-
piperazinocarbamoyl)-4,5,6,7-tetrahydroindazole (13)
References
1H NMR (CDCl3): l 1.25 (s, 3H, CH3); 1.80 (t, 4H,
CH2); 2.71 (t, 2H, CH2); 2.85 (t, 2H, CH2); 3.74 (t, 4H,
CH2–N–Me); 4.01 (t, 4H, N–CH2); 7.58–8.30 (m, 4H,
Ar).
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1H NMR (CDCl3): l 1.78 (t, 4H, CH2); 2.72 (t, 4H,
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(t, 2H, CH2); 7.20–7.50 (m, 4H, Ar).
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1H NMR (CDCl3): l 1.78 (t, 4H, CH2); 1.92 (t, 4H,
CH2); 2.70 (t, 2H, CH2); 2.84 (t, 2H, CH2); 3.65 (t, 4H,
N–CH2); 7.20–7.50 (m, 4H, Ar).

708
M.C. Cardia et al. / Il Farmaco 53 (1998) 698–708
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