Design, synthesis and biological activity of rigid cannabinoid CB1 receptor antagonists.

Article abstract of DOI:10.1248/cpb.50.1109

The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha, gamma-keto ester adduct (4). The optimal nitroderivativ

Full text of DOI:10.1248/cpb.50.1109

August 2002
Notes
Chem. Pharm. Bull. 50(8) 1109—1113 (2002)
1109
Design, Synthesis and Biological Activity of Rigid Cannabinoid CB1
Receptor Antagonists
Axel Reinhard STOIT, Jos Hubertus Maria LANGE,* Arnold Peter den HARTOG, Eric RONKEN,
Koos TIPKER, Herman Heinrich van STUIVENBERG, Jessica Adriana Rigtje DIJKSMAN,
Henri Cornelis WALS, and Chris Gerrit KRUSE
Solvay Pharmaceuticals, Research Laboratories; P.O. Box 900, 1380 DA Weesp, The Netherlands.
Received January 24, 2002; accepted April 19, 2002
The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2)
are described. The key synthetic step involves the ring closure of the lithiated a,g-keto ester adduct (4). The opti-
mal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pKi؍7.2) as well as very potent antag-
onistic activity (pA2؍8.8) in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on
the aromatic substitution pattern of the applied arylhydrazine.
Key words benzocycloheptapyrazole; CB1 receptor antagonist; molecular modeling; regiochemistry
Cannabinoids are present in the Indian hemp Cannabis Chemistry
sativa and have been used as medicinal agents for cen-
The four step synthesis route to the CB1 antagonists (2) is
turies.1,2) However, only within the past ten years the research exemplified by the preparation of 8 (Chart 1). Commercially
in the cannabinoid area has revealed pivotal information on available 1-benzosuberone (3) was deprotonated with lithium
CB receptors and their (endogenous) agonists. The discovery bis(trimethylsilyl)amide and subsequently reacted with di-
and the subsequent cloning3,4) of two subtypes of cannabi- ethyl oxalate to afford the lithiated keto ester adduct (4) as a
noid receptor (CB1 and CB2) stimulated the search for novel solid in 99% yield. Subsequent reaction with the arylhy-
cannabinoid antagonists and triggered the development of drazine (5) in acetic acid gave the benzocycloheptapyrazole
cannabinoid drugs for the treatment of diseases.5,6)
ester (6) in 51% yield. Mild basic hydrolysis of the car-
Several types of CB1 receptor antagonists are known (Fig. boethoxy group in 6 to the corresponding carboxylic acid
1). Sanofi disclosed7—9) their selective CB1 receptor antago-
roceeded quantitatively. 1-Ethyl-3-(3-dimethylaminopropyl)-
p
nist SR141716A (rimonabant) which is currently undergoing carbodiimide hydrochloride (EDC)-activated coupling to N-
clinical development for psychotic disorders and obesity aminoperhydroazepine (7) in dichloromethane furnished 8 in
treatment. Iodopravadoline AM-630 was introduced in 1995. 68% yield.
AM-630 is a moderately active CB1 receptor antagonist, but
In this specific case the pyrazole ring formation proceeds
sometimes behaves as a weak partial agonist.10) Researchers regioselectively to afford 6 as the sole product. However, as
from Eli Lilly described11) the selective CB1 receptor antago- we extended the scope to the reaction of Li-enolate (4) with
nist LY-320135. 3-Alkyl-5,5Ј-diphenylimidazolidinediones differently substituted arylhydrazines, it was found that the
were described as cannabinoid receptor ligands, which were regioselectivity in the pyrazole ring formation is very depen-
indicated12) to be cannabinoid antagonists. CP-272871 is a dent on the aromatic substitution pattern of the applied aryl-
pyrazole derivative, like SR141716A, but less potent and less hydrazine. This phenomenon21) is exemplified in Chart 2 for
CB1 receptor subtype-selective13) than SR141716A. Recently,
Aventis Pharma claimed14) diarylmethyleneazetidine analogs
(1) as CB1 receptor antagonists. Interestingly, many CB1 re-
ceptor antagonists have been reported15) to behave as inverse
agonists in vitro. Several reviews describe the current status
in the cannabinoid research area.16—19)
In this paper our approach to tricyclic selective CB1 recep-
tor antagonists of general formula (2) is described.20) We en-
visioned that an additional ring constraint from the 4-methyl
position in SR141716A to the ortho-position of its 5-aryl
substituent would provide a novel class of considerably more
rigid benzocycloheptapyrazoles (2), thereby having good
prospects as potent CB1 antagonists. Moreover, threedimen-
sional comparison of SR141716A with the more rigid coun-
terpart (2) and analysis of their pharmacological results is ex-
pected to provide a more detailed insight in the required
bioactive conformation of such CB1 receptor antagonists,
which is expected to facilitate their rational structure optimi-
sation.
Fig. 1. Chemical Structures of CB1 Receptor Antagonists
To whom correspondence should be addressed. e-mail: jos.lange@solvay.com
© 2002 Pharmaceutical Society of Japan

1110
Vol. 50, No. 8
a) LiHMDS, n-hexane; b) diethyl oxalate; c) 2,4-dichlorophenylhydrazine hydrochloride 5, HOAc; d) LiOH, THF, H2O; e) 1-aminohexa-
hydro-1H-azepine 7, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC).
Chart 1
was formed in 20% yield from 19 via a Sandmeyer reaction.
This low yield is due to partial overreduction of 20 to 21.
In this series a number of compounds was prepared for
pharmacological evaluation (Table 1).
Biological Evaluation and Discussion
The CB1 receptor affinities of thirteen compounds (8, 18,
20—30) were assessed in receptor binding studies (displace-
ment of the specific binding of the CB receptor ligand
[3H]CP-55,940 to the human CB1 receptor cloned in Chinese
hamster ovary (CHO) cells). CB1 receptor antagonistic activ-
ities were determined in a functional cell assay (blockade of
the CB agonist CP-55,940 induced c-AMP formation in
CHO cells, wherein the human CB1 receptor has been
cloned). CB1 receptor binding results are expressed as pKi
values. The CB1 antagonistic potencies of the compounds are
expressed as pA2 values.
The pharmacological results of the compounds (8, 18,
20—30) are summarized in Table 2.
Our investigations started with compound (21). This com-
pound is found less active than SR141716A in both assays.
Compound (8), wherein the piperidinyl ring of 21 is replaced
by the hexahydroazepinyl ring, behaves as a somewhat more
potent CB1 receptor antagonist in vitro as compared to 21.
However, this compound is still considerably less potent than
SR141716A. These findings prompted to design 20, which
a) 4-methoxyphenylhydrazine hydrochloride 9, HOAc.
Chart 2
the reaction of the Li-enolate (4) with 4-methoxyphenylhy- has exactly the aromatic chloro substitution pattern of
drazine (9). This reaction yielded a mixture of three products SR141716A. Compound (20) exhibits a decreased CB1 re-
(13), (14) and (15) in 15, 17 and 46% yield, respectively.
ceptor binding affinity as compared to the binding of
The formation of 13, 14 and 15 can be rationalised by in- SR141716A. However, its CB1 antagonistic potency is com-
voking the three pathways depicted in Chart 2. Reaction of parable. Compound (25) wherein the piperidinyl ring of 20 is
the enol tautomer (10a) with 4-methoxyphenylhydrazine (9) replaced by the hexahydroazepinyl ring shows the same ac-
leads to the hydrazone intermediate (11) which cyclises to tivity profile. Nitro substitution at the 8-position gives rise to
13. However, the reaction of the alternative enol tautomer 18 and 28, respectively. Both 18 and 28 are very potent CB1
(10b) with 9 gives the hydrazone (12). The resulting interme- receptor antagonists, showing nanomolar activities in our
diate (12) may cyclise via route a) to the pyrazole (14), or cy- CB1 functional assay.
clise via route b) to the hydroxypyridazinone analogue (15).
Structural comparison by molecular modeling analysis of
The corresponding reaction with 3-fluorophenylhydrazine the closest structural analogue (20) with SR141716A gives
gives the same regiochemical outcome. This observation sug- some interesting results (Fig. 2). Both 20 and SR141716A
gests that the regiochemistry of this cyclisation reaction is were minimised using the MOPAC/PM3 module of the
not simply governed by the electronic properties of the aryl SYBYL package, version 6.3 (Tripos Associates, Inc., St.
substituent(s) in the applied arylhydrazine. Further derivati- Louis, U.S.A.) on a Silicon Graphics Indigo2, Impact 10000.
sation of the benzocycloheptapyrazoles was accomplished
according to Chart 3.
As can be seen the difference in spatial conformation be-
tween both molecules is relatively small. This modeling re-
Nitration of the acid20) (16) gave a mixture of the 8- and 9- sult would predict comparable cannabinoid activities of the
nitroisomer (17) in a yield of 98%. Reaction of this mixture compounds. This is in line with the results from our func-
of regioisomers with 1-aminopiperidine in the presence of tional CB1 antagonist assay. However, SR141716A is consid-
HBTU, followed by HPLC separation of the resulting regioi- erably more potent than its tricyclic congeners in the CB1 re-
somers, furnished hydrazide (18) in 52% yield. Nitro group ceptor binding assay.
reduction afforded 19 in 91% yield. The hydrazide20) (20)
SR141716A has been reported9) orally active in vivo. It is

August 2002
1111
a) HNO3, HOAc; b) 1-aminopiperidine, HBTU; c) chromatographic separation of regioisomers; d) Fe/HCl, EtOH, H2O; e) NaNO2,
CuCl, H2O.
Chart 3
Table 1. Structural Formula of Prepared CB1 Receptor Antagonists
Compds.
R
X
n
8
18
20
21
22
23
24
25
26
27
28
29
30
H
8-NO2
8-Cl
H
H
H
CH2
CH2
CH2
CH2
CH2
O
3
2
2
2
4
2
3
3
2
3
3
2
3
H
O
8-Cl
9-Cl
9-Cl
8-NO2
9-NO2
9-NO2
CH2
CH2
CH2
CH2
CH2
CH2
Fig. 2. Molecular Modeling Results of SR141716A and 20
lipophilicity (LogP ca. 5.9). This bioavailability issue has to
be investigated in more detail.
In conclusion, benzocycloheptapyrazoles (2) constitute a
class of very potent CB1 receptor antagonists in vitro. The
bioavailability issue in this series of rigid cannabinoid recep-
tor antagonists deserves further attention.
Table 2. Pharmacological Results
a,b)
a,b)
Compds.
CB1 rb
CB1 funct
Experimental
1H- and 13C-NMR spectra were recorded on a Varian UN400 instrument
(400 MHz), using DMSO-d6 or CDCl3 with (CH3)4Si as an internal standard,
as solvents. Chemical shifts are given in ppm (d scale). Thin-layer chro-
matography was performed on Merck precoated 60 F254 plates, and spots
were visualised with UV light. Column chromatography was performed
using silica gel 60 (0.040—0.063 mm, Merck). Melting points were
recorded on a Büchi B-545 melting point apparatus and are uncorrected.
Mass spectra were recorded with a Micromass GCT or Kratos Concept 1S
instrument (compounds (8) and (15)).
SR141716A
7.6
7.0
6.8
6.9
6.4
6.7
6.3
6.4
6.9
6.6
6.5
7.2
6.3
7.1
8.6
7.5
8.9
8.5
7.2
7.2
7.0
7.0
8.8
7.3
7.4
8.8
7.8
7.3
8
18
20
21
22
23
24
25
26
27
28
29
30
1-(2,4-Dichlorophenyl)-N-(hexahydro-1H-azepin-1-yl)-1,4,5,6-tetrahy-
drobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (8) To a cooled
solution (0 °C) of 1620) (0.70 g, 1.88 mmol) in dichloromethane (15 ml) was
successively added 1-aminohexahydro-1H-azepine (0.24 ml, 2.07 mmol) and
EDC (0.4 g, 2.09 mmol). The resulting solution was allowed to attain room
temperature and stirred for 48 h. After addition of brine, followed by extrac-
tion with CHCl3, the organics were washed with brine and dried over
Na2SO4. The product was purified by column chromatography (Et2O/petro-
a) CB1 rb: CB1 receptor binding (pKi): CB1 funct: CB1 functional cell assay (pA2).
b) All pKi and pA2 values are mean values from at least three independent experiments.
1
leum etherϭ1/2 (v/v)) to give 8 (0.60 g, 68%), mp 115—118 °C. H-NMR
(CDCl3) d: 1.62—1.68 (m, 4H), 1.72—1.82 (m, 4H), 2.22—2.30 (m, 2H),
2.69 (t, Jϭ7 Hz, 2H), 2.80—3.12 (m, 2H), 3.15—3.19 (m, 4H), 6.65 (br d,
Jϭ8 Hz, 1H), 7.03 (td, Jϭ8, 2 Hz, 1H), 7.21 (td, Jϭ8, 2 Hz, 1H), 7.30 (br d,
Jϭ8 Hz, 1H), 7.39 (dd, Jϭ8, 2 Hz, 1H), 7.44 (d, Jϭ2 Hz, 1H), 7.47 (d,
Jϭ8 Hz, 1H), 8.13 (br s, 1H). 13C-NMR (DMSO-d6) d: 20.0, 26.7, 26.9,
31.8, 32.1, 57.7, 121.3, 126.5, 127.1, 128.89, 128.92, 129.1, 130.1, 130.2,
132.15, 132.23, 135.2, 136.4, 141.6, 142.9, 144.0, 159.9. Electron impact
(EI)-MS m/z: 468 (Mϩ) (9), 355 (25), 98 (100). High resolution (HR)-EI-
MS m/z: 468.1527 (Calcd for C25H26Cl2N4O: 468.1484).
interesting to note that compound (20) showed neither in vivo
activity after oral nor i.p. dosing These results prompted to
investigate the bioavailability in our series CB1 antagonists of
general formula (2) in more detail. After administration of
compound (8), blood plasma levels in rat were found negligi-
ble (Ͻ50 ng/ml) at 1 h after p.o. (30 mg/kg) and i.p. adminis-
tration (30 mg/kg), respectively. The low bioavailability of 8
might be ascribed22) to either its low rate of water dissolution
Synthesis of 13, 14 and 15 Lithium hexamethyldisilazide (83 ml, 1 M
solution in n-hexane (THF)) was dissolved in dry Et2O (250 ml) at Ϫ78 °C
in combination with a poor water solubility or its high under a nitrogen atmosphere. A solution of 1-benzosuberone (13.3 g,

1112
Vol. 50, No. 8
83.1 mmol) in dry ether (50 ml) was slowly added. The resulting
ethylacetate layer was separated, washed with water, dried over Na2SO4, fil-
solution is stirred for 30 min at Ϫ73 °C and 15 min at 0 °C and cooled to tered and concentrated in vacuo to afford crude 19 (2.83 g). Column chro-
Ϫ78 °C. A solution of dimethyl oxalate (11.0 g, 93 mmol) in Et2O/THF was matography (CH2Cl2/acetoneϭ4/1 (v/v)) gave the intermediate 19 (2.50 g,
quickly added. The resulting mixture was allowed to attain room tempera- 91%) as a syrup. Addition of 19 (2.50 g, 5.32 mmol) to cooled concentrated
ture and stirred overnight. The formed precipitate (4) (20.9 g, 99%) was col-
lected by filtration and thoroughly washed with Et2O. Part of the precipitate (0.37 g, 5.37 mmol) in water (2 ml). This solution was stirred at 0 °C for
(1.3 g, 4.89 mmol) was dissolved in acetic acid (20 ml), followed by addition 30 min and quickly added to a cooled solution of CuCl (0.27 g, 2.75 mmol)
HCl (40 ml) was followed by addition at 0 °C of a solution of NaNO2
of 4-methoxyphenylhydrazine hydrochloride (0.80 g, 4.58 mmol). The re- in concentrated HCl (5 ml). The resulting mixture was heated at 55 °C for
sulting mixture was heated at 100 °C for 15 min, concentrated in vacuo, fol- 1 h, cooled to room temperature, followed by addition of ice and ethylac-
lowed by ethylacetate addition. The organics were washed with saturated etate. A mixture of ice and concentrated NaOH was added. The ethylacetate
NaHCO3 solution and dried over Na2SO4. Separation by column chromatog- layer was separated and the water layer extracted with ethylacetate. The
raphy (Et2O/petroleum etherϭ1/3 (v/v)) gave pure 13 (0.25 g, 15%) and 14
(0.28 g, 17%), respectively, followed by elution with (MeOH/ethylace- dried over Na2SO4, filtered and concentrated in vacuo. The residue was dis-
tateϭ1/4 (v/v/)) to give 15 (0.7 g, 46%). solved in diethyl ether and impurities removed by filtration and the filtrate
combined ethylacetate layers were filtered over hyflo, washed with water,
Ethyl 1-(4-Methoxyphenyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2- was concentrated in vacuo. Column chromatograpy (CH2Cl2/acetoneϭ9/1
c]pyrazole-3-carboxylate (13): mp 95—97 °C. 1H-NMR (DMSO-d6) d: 1.35 (v/v)) gave 20 (0.51 g, 20%) and 21 (0.29 g, 12%), respectively. Compound
1
(t, Jϭ7 Hz, 3H), 2.13—2.22 (m, 2H), 2.68 (t, Jϭ7 Hz, 2H), 2.75 (t, Jϭ7 Hz, (20): mp 204—205 °C, lit.20) mp 202 °C. H-NMR (CDCl3) d: 1.40—1.48
2H), 3.80 (s, 3H), 4.34 (q, Jϭ7 Hz, 2H), 6.71 (d, Jϭ8 Hz, 1H), 6.97 (d, (m, 2H), 1.71—1.80 (m, 4H), 2.20—2.30 (m, 2H), 2.66 (t, Jϭ7 Hz, 2H),
Jϭ8 Hz, 2H), 7.08 (t, Jϭ8 Hz, 1H), 7.22—7.28 (m, 3H), 7.38 (d, Jϭ8 Hz, 2.82—2.91 (m, 4H), 3.00—3.40 (m, 2H), 6.57 (d, Jϭ8 Hz, 1H), 7.00 (dd,
1H). EI-MS m/z: 362 (Mϩ) (70), 316 (45), 289 (88), 288 (100). HR-EI-MS
m/z: 362.1637 (Calcd for C22H22N2O3: 362.1630).
Jϭ8, 2 Hz, 1H), 7.30 (d, Jϭ2 Hz, 1H), 7.41 (dd, Jϭ8, 2 Hz, 1H), 7.44 (d,
Jϭ2 Hz, 1H), 7.47 (d, Jϭ8 Hz, 1H), 7.68 (br s, 1H). EI-MS m/z: 488 (Mϩ)
Ethyl 2-(4-Methoxyphenyl)-2,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2- (15), 389 (57), 362 (82), 360 (76), 84 (100). HR-EI-MS m/z: 488.0901
1
c]pyrazole-3-carboxylate (14): mp 89 °C. H-NMR (DMSO-d6) d: 1.14 (t, (Calcd for C24H23Cl3N4O: 488.0937).
Jϭ7 Hz, 3H), 2.02—2.10 (m, 2H), 2.79—2.85 (m, 2H), 3.01 (t, Jϭ7 Hz,
2H), 3.84 (s, 3H), 4.17 (q, Jϭ7 Hz, 2H), 7.01 (d, Jϭ8 Hz, 2H), 7.21—7.26
1-(2,4-Dichlorophenyl)-N-(piperidin-1-yl)-1,4,5,6-tetrahydrobenzo-
[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (21) Procedure as for the
(m, 3H), 7.37 (d, Jϭ8 Hz, 2H), 7.93—7.98 (m, 1H). EI-MS m/z: 362 (Mϩ) preparation of compound (8) gave 21, mp 167—169 °C, lit.20) mp 170 °C.
(100), 333 (35), 289 (24). HR-EI-MS m/z: 362.1653 (Calcd for C22H22N2O3: 1H-NMR (CDCl3) d: 1.39—1.47 (m, 2H), 1.71—1.79 (m, 4H), 2.21—2.30
362.1630).
(m, 2H), 2.68 (t, Jϭ7 Hz, 2H), 2.80—3.30 (m, 6H), 6.64 (br d, Jϭ8 Hz, 1H),
7.01 (td, Jϭ8, 2 Hz, 1H), 7.20 (td, Jϭ8, 2 Hz, 1H), 7.29 (br d, Jϭ8 Hz, 1H),
7.39 (dd, Jϭ8, 2 Hz, 1H), 7.43 (d, Jϭ2 Hz, 1H), 7.46 (d, Jϭ8 Hz, 1H), 7.68
(br s, 1H). EI-MS m/z: 454 (Mϩ) (10), 355 (55), 326 (90), 84 (100). HR-EI-
4-Hydroxy-2-(4-methoxyphenyl)-2,5,6,7-tetrahydro-3H-benzo[6,7]cyclo-
hepta[1,2-c]pyridazin-3-one (15): mp Ͼ245 °C. 1H-NMR (DMSO-d6, 120 °C)
d: 1.94—2.02 (m, 2H), 2.43 (t, Jϭ7 Hz, 2H), 2.60 (t, Jϭ7 Hz, 2H), 3.80 (s,
3H), 6.92 (d, Jϭ8 Hz, 2H), 7.16—7.30 (m, 3H), 7.51 (dd, Jϭ8, 2 Hz, 1H), MS m/z: 454.1288 (Calcd for C24H24Cl2N4O: 454.1327).
7.57 (d, Jϭ8 Hz, 2H), 4-OH proton is not visible. 13C-NMR (DMSO-d6) d:
N-(Azocan-1-yl)-1-(2,4-dichlorophenyl)-1,4,5,6-tetrahydrobenzo[6,7]-
cyclohepta[1,2-c]pyrazole-3-carboxamide (22) Procedure as for the
20.9, 29.2, 31.1, 55.2, 113.2, 126.1, 126.5, 127.6, 128.3, 128.4, 135.5, 137.8,
138.9, 151.6, 158.0, 161.5, 162.8. EI-MS m/z: 334 (Mϩ) (100). HR-EI-MS preparation of compound (8) gave 22, mp 118 °C. 1H-NMR (CDCl3) d:
m/z: 334.1356 (Calcd for C20H18N2O3: 334.1317).
Synthesis of 18 and 29 Pure nitric acid (40 ml) is slowly added to (m, 2H), 3.10—3.16 (m, 4H), 6.65 (br d, Jϭ8 Hz, 1H), 7.02 (td, Jϭ8, 2 Hz,
cooled (0 °C) acetic acid (40 ml). Acid (16)20) (13.77 g, 36.9 mmol) is added
1H), 7.21 (td, Jϭ8, 2 Hz, 1H), 7.30 (br d, Jϭ8 Hz, 1H), 7.38 (dd, Jϭ8, 2 Hz,
1.64—1.76 (m, 10H), 2.22—2.31 (m, 2H), 2.68 (t, Jϭ7 Hz, 2H), 2.76—3.06
and the resulting mixture is stirred at room temperate overnight and poured 1H), 7.43 (d, Jϭ2 Hz, 1H), 7.46 (d, Jϭ8 Hz, 1H), 8.18 (br s, 1H). EI-MS
onto ice. The formed precipitate is collected by filtration, washed with water m/z: 482 (7), 355 (75), 112 (100). (Mϩ) HR-EI-MS m/z: 482.1616 (Calcd for
and dried to give crude 17 (15.12 g, 98%) which consists of the 8-nitro and 9 C26H28Cl2N4O: 482.1640).
nitro-regiosomer in a molar ratio of 4 : 3. To a suspension of crude 17
(6.27 g, 0.015 mol) in dry acetonitrile (120 ml) is successively added diiso- drobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (23) Procedure
propyl ether (5.75 ml, 0.033 mol), HBTU (6.82 g, 0.018 mol) and 1- as for the preparation of compound (8) starting from 1-oxa-5-benzosuberone
1-(2,4-Dichlorophenyl)-6-oxa-N-(piperidin-1-yl)-1,4,5,6-tetrahy-
1
aminopiperidine (1.94 ml, 0.018 mol) and the resulting mixture is stirred at gave 23 as an amorphous solid. H-NMR (CDCl3) d: 1.38—1.45 (m, 2H),
room temperature overnight. The mixture is concentrated in vacuo and the 1.68—1.78 (m, 4H), 2.80—2.88 (m, 4H), 3.47 (t, Jϭ7 Hz, 2H), 4.38 (t,
residue is dissolved in ethylacetate, washed with water, dried over Na2SO4,
Jϭ7 Hz, 2H), 6.67 (br d, Jϭ8 Hz, 1H), 6.80 (td, Jϭ8, 2 Hz, 1H), 7.11 (br d,
filtered and concentrated in vacuo. Chromatographic purification (Et2O) Jϭ8 Hz, 1H), 7.17 (td, Jϭ8, 2 Hz, 1H), 7.31 (d, Jϭ8 Hz, 1H), 7.36 (dd, Jϭ8,
gave 18 (3.90 g, 52%) and 29 (2.21 g, 29%), respectively.
2 Hz, 1H), 7.52 (d, Jϭ2 Hz, 1H), 7.65 (br s, 1H). EI-MS m/z: 456 (Mϩ) (8),
358 (100), 84 (74). HR-EI-MS m/z: 456.1111 (Calcd for C23H22Cl2N4O2:
1-(2,4-Dichlorophenyl)-8-nitro-N-(piperidin-1-yl)-1,4,5,6-tetrahydrobenzo-
[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (18): mp 179—182 °C. 1H- 456.1120).
NMR (CDCl3) d: 1.42—1.48 (m, 2H), 1.70—1.82 (m, 4H), 2.26—2.36 (m,
2H), 2.76—2.92 (m, 6H), 3.20—3.60 (m, 2H), 6.80 (d, Jϭ8 Hz, 1H), 7.42—
7.55 (m, 3H), 7.67 (br s, 1H), 7.90 (dd, Jϭ8, 2 Hz, 1H), 8.20 (d, Jϭ2 Hz,
1H). 13C-NMR (DMSO-d6) d: 20.4, 23.7, 26.1, 31.7, 32.2, 55.9, 122.1,
1-(2,4-Dichlorophenyl)-N-(hexahydro-1H-azepin-1-yl)-6-oxa-1,4,5,6-
tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (24) Pro-
cedure as for the preparation of compound (8) starting from 1-oxa-5-benzo-
1
suberone gave 24 as an amorphous solid. H-NMR (CDCl3) d: 1.60—1.67
123.2, 125.2, 128.6, 129.5, 130.5, 132.2, 132.5, 135.9, 136.07, 136.12, (m, 4H), 1.71—1.79 (m, 4H), 3.12—3.17 (m, 4H), 3.49 (t, Jϭ7 Hz, 2H),
141.3, 144.0, 144.6, 147.5, 159.7. EI-MS m/z: 499 (Mϩ) (12), 400 (100), 4.40 (t, Jϭ7 Hz, 2H), 6.69 (br d, Jϭ8 Hz, 1H), 6.82 (td, Jϭ8, 2 Hz, 1H), 7.12
371 (65), 84 (36). HR-EI-MS m/z: 499.1159 (Calcd for C24H23Cl2N5O3:
499.1178).
(br d, Jϭ8 Hz, 1H), 7.19 (td, Jϭ8, 2 Hz, 1H), 7.32 (d, Jϭ8 Hz, 1H), 7.37 (dd,
Jϭ8, 2 Hz, 1H), 7.52 (d, Jϭ2 Hz, 1H), 8.10 (br s, 1H). EI-MS m/z: 470
(Mϩ) (6), 358 (92), 98 (100). HR-EI-MS m/z: 470.1255 (Calcd for
1-(2,4-Dichlorophenyl)-9-nitro-N-(piperidin-1-yl)-1,4,5,6-tetrahydrobenzo-
[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (29): mp 201—203 °C. 1H- C24H24Cl2N4O2: 470.1276).
NMR (CDCl3) d: 1.40—1.48 (m, 2H), 1.73—1.80 (m, 4H), 2.22—2.38 (m,
8-Chloro-1-(2,4-dichlorophenyl)-N-(hexahydro-1H-azepin-1-yl)-
2H), 2.81 (t, Jϭ7 Hz, 2H), 2.85—2.91 (m, 4H), 3.20—3.60 (m, 2H), 7.43 (d, 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide
Jϭ2 Hz, 1H), 7.45—7.51 (m, 2H), 7.54 (d, Jϭ2 Hz, 1H), 7.59 (d, Jϭ8 Hz, (25) Procedure as for the preparation of compound (20) gave 25, mp
1H), 7.67 (br s, 1H), 8.07 (dd, Jϭ8, 2 Hz, 1H). EI-MS m/z: 499 (Mϩ) (11), 162—164 °C. 1H-NMR (CDCl3) d: 1.60—1.68 (m, 4H), 1.72—1.81 (m,
400 (70), 371 (59), 99 (62), 84 (100). HR-EI-MS m/z: 499.1168 (Calcd for 4H), 2.21—2.31 (m, 2H), 2.66 (t, Jϭ7 Hz, 2H), 3.14—3.50 (m, 6H), 6.57 (d,
C24H23Cl2N5O3: 499.1178).
Jϭ8 Hz, 1H), 7.01 (dd, Jϭ8, 2 Hz, 1H), 7.30 (d, Jϭ2 Hz, 1H), 7.40 (dd,
Jϭ8, 2 Hz, 1H), 7.44 (d, Jϭ2 Hz, 1H), 7.47 (d, Jϭ8 Hz, 1H), 7.80—8.60 (m,
8-Chloro-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1,4,5,6-tetrahy-
drobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (20) Iron pow- 1H). EI-MS m/z: 502 (Mϩ) (8), 389 (78), 98 (100). HR-EI-MS m/z:
der (3.5 g) was suspended in a mixture of water (40 ml) and ethanol (15 ml).
HCl (2.2 ml, 1 N) was added and the resulting mixture was stirred at 50 °C.
502.1086 (Calcd for C25H25Cl3N4O: 502.1094).
9-Chloro-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1,4,5,6-tetrahy-
After addition of 18 (2.91 g, 5.82 mmol) the mixture was heated for 3 h at drobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (26) Procedure
65 °C. After cooling to room temperature ethylacetate and water were added as for the preparation of compound (20) gave 26, mp 232—234 °C. 1H-NMR
and the iron-containing precipitate was removed by filtration over hyflo. The (CDCl3) d: 1.40—1.48 (m, 2H), 1.72—1.80 (m, 4H), 2.20—2.30 (m, 2H),

August 2002
1113
I., Nature (London), 356, 561—564 (1990).
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2.65 (t, Jϭ7 Hz, 2H), 2.84—3.40 (m, 6H), 6.61 (d, Jϭ2 Hz, 1H), 7.18 (dd,
Jϭ8, 2 Hz, 1H), 7.23 (d, Jϭ8 Hz, 1H), 7.43 (dd, Jϭ8, 2 Hz, 1H), 7.46 (d,
Jϭ2 Hz, 1H), 7.50 (d, Jϭ8 Hz, 1H), 7.64—7.74 (m, 1H). EI-MS m/z: 488
(Mϩ) (6), 362 (37), 84 (100). HR-EI-MS m/z: 488.0921 (Calcd for
C24H23Cl3N4O: 488.0937).
9-Chloro-1-(2,4-dichlorophenyl)-N-(hexahydro-1H-azepin-1-yl)-
1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide
(27) Procedure as for the preparation of compound (20) gave 27, mp
150 °C. 1H-NMR (CDCl3) d: 1.62—1.67 (m, 4H), 1.72—1.80 (m, 4H),
2.20—2.28 (m, 2H), 2.65 (t, Jϭ7 Hz, 2H), 3.14—3.18 (m, 4H), 3.50—3.80
(m, 2H), 6.61 (d, Jϭ2 Hz, 1H), 7.18 (dd, Jϭ8, 2 Hz, 1H), 7.23 (d, Jϭ8 Hz,
1H), 7.43 (dd, Jϭ8, 2 Hz, 1H), 7.46 (d, Jϭ2 Hz, 1H), 7.49 (d, Jϭ8 Hz, 1H),
8.45 (br s, 1H). EI-MS m/z: 502 (Mϩ) (6), 389 (62), 98 (100). HR-EI-MS
m/z: 502.1049 (Calcd for C25H25Cl3N4O: 502.1094).
1-(2,4-Dichlorophenyl)-N-(hexahydro-1H-azepin-1-yl)-8-nitro-1,4,5,6-
tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (28) Pro-
cedure as for the preparation of compound (18) gave 28 as an amorphous
solid. 1H-NMR (CDCl3) d: 1.62—1.68 (m, 4H), 1.70—1.82 (m, 4H), 2.26—
2.37 (m, 2H), 2.80 (t, Jϭ7 Hz, 2H), 3.14—3.18 (m, 4H), 3.22—3.56 (m,
2H), 6.80 (d, Jϭ8 Hz, 1H), 7.42—7.46 (m, 2H), 7.53 (d, Jϭ8 Hz, 1H), 7.89
(dd, Jϭ8, 2 Hz, 1H), 8.12 (br s, 1H), 8.19 (d, Jϭ2 Hz, 1H). EI-MS m/z: 513
(Mϩ) (7), 400 (47), 98 (100). HR-EI-MS m/z: 513.1291 (Calcd for
C25H25Cl2N5O3: 513.1334).
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1-(2,4-Dichlorophenyl)-N-(hexahydro-1H-azepin-1-yl)-9-nitro-1,4,5,6-
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(2000).
t
etrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide (30) Pro-
cedure as for the preparation of compound (29) gave 30, mp 191—193 °C.
1H-NMR (CDCl3) d: 1.62—1.70 (m, 4H), 1.72—1.80 (m, 4H), 2.25—2.35
(m, 2H), 2.70—2.90 (m, 4H), 3.14—3.20 (m, 4H), 7.42—7.50 (m, 3H), 7.54
(d, Jϭ2 Hz, 1H), 7.59 (d, Jϭ8 Hz, 1H), 8.07 (dd, Jϭ8, 2 Hz, 1H), 8.11 (br s,
1H). EI-MS m/z: 513 (Mϩ) (19), 400 (89), 371 (32), 98 (100). HR-EI-MS
m/z: 513.1318 (Calcd for C25H25Cl2N5O3: 513.1334).
20) During the preparation of this manuscript a group from Sanofi-Synthe-
labo published a patent application wherein the synthesis of struc-
turally related tricyclic compounds is mentioned. Barth F., Congy C.,
Martinez S., Rinaldi M., Patent WO 01 32,663 (2001) [Chem. Abstr.,
134, 340504 (2001)].
Acknowledgements Mrs. Alice Borst and Mr. Karel Stegman are grate-
fully acknowledged for supply and interpretation of the spectral data.
References and Notes
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