The synthesis and vasopressin (AVP) antagonist activity of a novel series of N-Aroyl-2,4,5,6-tetrahydropyrazolo-[3,4-d]thieno[3,2-b]azepines

Article abstract of DOI:10.1016/S0960-894X(00)00084-6

Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl)carbonyl]phenyl]be nzamides as arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00084-6

Bioorganic & Medicinal Chemistry Letters 10 (2000) 695±698
The Synthesis and Vasopressin (AVP) Antagonist Activity
of a Novel Series of N-Aroyl-2,4,5,6-tetrahydropyrazolo-
[3,4-d]thieno[3,2-b]azepines
J. Donald Albright,* Efren G. Delos Santos, John P. Dusza, Peter S. Chan,
Joseph Coupet, Xun Ru and H. Mazandarani
Chemical Sciences, Wyeth-Ayerst Research, 401 N, Middletown Road, Pearl River, NY 10965, USA
Received 19 November 1999; accepted 17 January 2000
AbstractÐSynthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl)carbonyl]phenyl]benzamides as
arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when
the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine
and VPA-985 are reported. # 2000 Elsevier Science Ltd. All rights reserved.
One of the components in the regulation of body ¯uid is
the hormone arginine vasopressin (AVP) which regu-
lates solute free water clearance. Vasopressin (anti-
diuretic hormone) interacts at the V2 receptors in the
collecting ducts (aquaporin-2 water channels) of the
kidney to control water reabsorption and in this manner
helps to regulate salt (NaCl) balance via antidiuresis.1 3
Thus a vasopressin antagonist (as opposed to a con-
ventional diuretic) would be the drug of choice to nor-
malize plasma osmolality and control hyponatremia
which occurs in congestive heart failure, liver cirrhosis
and renal failure.
We wish to report on derivatives of the tricyclic hetero-
cycle 2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]aze-
pine which are potent AVP receptor antagonists. The
4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine-5-one 519,20
was synthesized from 4-oxo-4,5,6,7-tetrahydrobenzo-
[b]thiophene (1) (Scheme 1). Reaction with hydroxyl-
amine gave the syn and anti oximes 2 and 319,20 which
were reacted with tosyl chloride to give the oxime-O-
tosylate (4). Rearrangement a€orded 5 in 55% overall
yield. Reduction of the lactam with borane±dimethyl-
sul®de gave 6 (85%) while reduction with LAH in
tetrahydrofuran gave a lower yield of 6 (60%). Reaction
of 6 with either 4-nitrobenzoyl chloride or 2-chloro-4-
nitrobenzoyl chloride gave 7 and 8, respectively. Intro-
duction of the 5-oxo group was carried out with
The development of peptide and nonpeptide V1a and V2
vasopressin receptor antagonists has been reviewed4 and
the synthesis and activity of the clinical VPA antagonist,
5-¯uoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodi-
azepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide
(21a) (VPA-985) and analogues have been reported.5
Derivatives of the tricyclic ring systems, 4,10-dihydro-
5H-thieno[3,2-c][1]benzazepine and 9,10-dihydro-4H-
thieno[2,3-c][1]benzazepine, with a thiophene ring fused
to a benzazepine moiety have been reported as potent
and orally active AVP antagonists.6 The nonpeptide
bicyclic benzazepine OPC-312607 15 and the tricyclic
benzazepine YM-08716 18 have been disclosed as vaso-
pressin antagonists which are orally active aquaretics.
21
KMnO4 in acetone±water (modi®ed literature proce-
dure) to give keto intermediates 9 and 10.22
The derivatives 9 and 10 were reacted with Bredereck's
Reagent (tert-butoxybis(dimethylamino)methane) to
a€ord the dimethylaminomethylene ketones 11 and 12.
Reaction with either hydrazine or methylhydrazine gave
the tricyclic 6-(4-nitrobenzoyl)pyrazolo[3,4-d]thieno[3,2-
b]azepines 13 and 14, which were reduced to give the
intermediate 6-(4-aminobenzoyl)pyrazolo[3,4-d]thieno-
[3,2-b]azepines 15.22 The nitro group in compounds
without a chloro group was reduced by heating with
Pd/C-hydrazine in ethanol. However, nitro derivatives
such as 14 with a chlorine atom were reduced with
stannous chloride in ethanol in order to avoid partial
dechlorination induced with Pd/C-hydrazine in ethanol.
*Corresponding author. Tel.: +1-914-732-3966; fax: +1-914-732-
5561; e-mail: albrigj@war.wyeth.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00084-6

696
J. D. Albright et al. / Bioorg. Med. Chem. Lett. 10 (2000) 695±698
As shown in Scheme 2, the 4-aminobenzoyl derivatives
15 were reacted with acid chlorides (R2COCl) to obtain
analogues 17 and 18. Diacylation occurs on acylation of
the tricyclic pyrazoles with a free NH group to a€ord
intermediates 16 which were deacylated with sodium
hydroxide to give the unsubstituted pyrazoles.
the same 2-chloro-4-(2-methyl-5-¯uorobenzoylamino)-
benzoyl `tail unit' as 21a (VPA-985).5a
For comparison purposes, derivatives 20a±e lacking the
fused pyrazole ring were synthesized as shown in
Scheme 3.23 The analogue 20a similar to 17d with the
same `tail unit' as 21a (VPA-985) also lacked in vivo
activity. A signi®cant ®nding is the increased binding
activity and the potent in vivo (po) activity with deri-
vatives 17f, 20c±e, 21c and 21d24 which all have a ter-
minal 2-phenylbenzoyl moiety.
As shown in Table 1, the analogues 17a±e exhibited
moderate binding selectivity for rat V2 receptors versus
rat V1 receptors and all except 17d exhibited in vivo
(po) aquaretic activity. The analogues 18a±c with an
N-methyl group on the pyrazole ring exhibited sig-
ni®cant binding activity for rat V2 receptors; however,
they exhibited little or no in vivo (po) aquaretic activ-
ity. Notable is the lack of oral activity for 17d which has
We have shown that potent in vivo activity (aquaresis)
is dependent not only on the `head unit' but also on the
substituent groups in the terminal benzoyl moiety. A
Scheme 1. (a) NH2OH.HCl/NaOAc[EtOH/H2O] (99%); (b) TsCl/pyridine (92%); (c) KOAc/EtOH/H2O (60%); (d) THF/BH3.S(CH3)2 (91%); (e)
Et3N/CH2Cl2; (f) KMnO4/MgSO4[acetone/H2O (70 ꢀC]; (g) Brederick's Reagent; (h) NH2NH2 or NH2NH(CH3).
Scheme 2.

J. D. Albright et al. / Bioorg. Med. Chem. Lett. 10 (2000) 695±698
697
Scheme 3. (a) Pd/C-HOAc; H2; (b) SnCl2.2H2O/EtOH; (c) NCS; (d) Fe/HOAc; 6N HCl; (e) R2COCl/Et3N/CH2Cl2.
Table 1. In vitro and in vivo antagonist activity
IC50 (nM)a
(r)=rat (h)=human (receptors)
Urine volume
mL/4 h
No.
R
R1
R2
V1a
V2
17a
17b
17c
17d
17e
17f
18a
18b
18c
18d
20a
20b
20c
20d
20e
21a
21b
21c
21d
H
H
H
H
H
H
H
H
Cl
Cl
Cl
H
H
H
H
Cl
H
Cl
H
Cl
Cl
H
Cl
H
2-CH3-Ph
2-Cl-4-F-Ph
2-CH3-5-F-Ph
2-CH3-5-F-Ph
2-F-5-Cl-Ph
2-(Ph)-Ph
(r) 2100
(r) 2000
(r) 1700
(r) 12,400
(h) 240
(h) Ðb
(h) Ð
(h) 69%c
(h) Ð
Ð
(h) 1740
(h) 4100
(h) Ð
(h) 88%c
(h) 110
(h) Ð
(h) 86
(h) 82
Ð
(r) 120
(r) 340
(r) 69
(r) 6
(h) 130
(h) 140
(h) 71
(h) Ð
(h) Ð
(h) 1.7
(h) 220
(h) 150
(h) Ð
(h) 88%c
(h) 3.4
(h) Ð
(h) Ð
(h) Ð
Ð
21e
15f
18e
7f
12f
c
(r) 18%
(r) 36
(r) Ð
(r) 24
(r) 38
(r) 230
(r) Ð
(r) Ð
(r) 19
(r) 1.2
(r) 3.2
Ð
H
27f (22)d
3f
CH3
CH3
CH3
COR2
H
Cl
H
Cl
Cl
Ð
Ð
Ð
2-CH3-Ph
(r) 2010
(r) 2100
(r) 4700
(r) Ð
2-Cl-4-Cl-Ph
cyclohexyl
2-CH3-Ph
2-CH3-5-F-Ph
2-Cl-4-Cl-Ph
2-(Ph)-Ph
2-(Ph)-Ph
2-(Ph)-Ph
2-CH3-5-F-Ph
2-Cl-4-Cl-Ph
2-(Ph)-Ph
6e
9e
14e
(r) Ð
4e
(r) 230
(r) Ð
(r) Ð
8e
19f
20f
22f
(r) 340
(r) 23
(r) 16
(r) 3.4
(h) 230
(h) 15
(h) 370
(h) Ð
(r) 2.3
(r) 3.1
(r) 1.5
(r) 2.6
(h) 1.2
(h) 3.2
(h) 2.7
(h) Ð
22f (20)d
16e
27f (20)d
21f
Ð
2-(Ph)-Ph
aSee ref 5a for V1a, V2 receptor binding procedures.
bNot tested.
c% Inhibition at 10 mM.
dUrine volume at a dose of 3 mg/kg.
eWater-loaded (30 mL/kg)+0.4 mg/kg of AVP (ip) (see ref 5a); urine volume of controls 5±6 mL.
fTest compounds were given at an oral dose of 10 mg/kg in a volume of 10 mL/kg (20% dimethylsulfoxide in 2.5% preboiled starch). During the
test, rats were not provided with water or food. Urine was collected for 4 h after dosing of the compound. At the end of 4 h, urine volume was
measured; volume of controls 7±9 mL.
signi®cant ®nding is the enhanced in vivo (po) activity
across three di€erent `head units' when a 2-phenyl-
benzoyl group was substituted for a 2-methyl-5-¯uoro-
benzoyl group in the `tail unit' to give compounds with
activity equivalent to or greater than the clinical com-
pound (VPA-985).
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