A novel trifluoromethanesulfonamidophenyl-substituted quinoline derivative, GA 0113: Synthesis and pharmacological profiles

Article abstract of DOI:10.1016/S0022-1139(01)00383-9

The trifluoromethanesulfonamidophenyl-substituted quinoline GA 0113 have been synthesized from o-nitrobenzoyl chloride via a multi-step process. GA 0113 displaced specific binding of [¹²⁵I]-Sar1, Ile⁸-Ang II to AT₁ receptors in membrane from Sf9 cells. In concious normotensive dogs, GA 0113 inhibited the Ang II-induced pressor response with ID₅₀ of 0.032mg/kg and dose-dependently increased plasma renin activity for 48h.

Full text of DOI:10.1016/S0022-1139(01)00383-9

Journal of Fluorine Chemistry 109 <2001) 83±86
Review
A novel tri¯uoromethanesulfonamidophenyl-substituted quinoline
derivative, GA 0113: synthesis and pharmacological pro®les
a
Yoshitomi Morizawaa,*, Takashi Okazoea, Shu-zhongWang , Jun Sasakia,
Hajime Ebisub, Masakuni Nishikawab, Hiroshi Shinyamab
aResearch Center, Asahi Glass Co. Ltd., 1150 Hazawa-cho, Kanagawa-ku, Yokohama 221-8755, Japan
bPharmaceutical Research Division, WelFide Corporation, 25-1 Shodai-Ohtani 2-Chome, Hirakata, Osaka 573-1153, Japan
Accepted 16 January 2001
Abstract
The tri¯uoromethanesulfonamidophenyl-substituted quinoline GA 0113 have been synthesized from o-nitrobenzoyl chloride via a multi-
step process. GA 0113 displaced speci®c bindingof ‰125IŠ-Sar1, Ile8-AngII to AT receptors in membrane from Sf9 cells. In concious
1
normotensive dogs, GA 0113 inhibited the Ang II-induced pressor response with ID50 of 0.032 mg/kg and dose-dependently increased
plasma renin activity for 48 h. # 2001 Elsevier Science B.V. All rights reserved.
Keywords: <Tri¯uoromethylsulfonamidophenyl)quinoline; Angiotensin-II receptor antagonist; Antihypertensive drug; MOPACTM
1. Introduction
capitalizingon the enhanced bindingaf®nity [4,5]. On the
other hand, much attention has been paid to the replacement
of aryltetrazole group as a means for improving the rela-
tively low oral bioavailability. AII antagonists incorporating
squaric acid, acylsulfonamides, tri¯uoromethansulfonamide
<tri¯amide) [6,7], and acidic heterocycle moieties have
recently been reported. Our strategy was to ®nd a novel
biphenyltetrazole replacement, and we describe herein the
synthesis and pharmacological activity of the new potent
nonpeptide nontetrazole AII receptor antagonist, designated
GA 0113, which carries a tri¯amide group as a more
lipophilic acidic group and a quinoline moiety.
The renin±angiotensin system <RAS) is well known to
play an important role in blood pressure regulation and
electrolyte homeostasis, and has the octapeptide angiotensin
II <AII) as its principal active hormone [1]. The prevention of
the formation of AII from angiotensin I <AI) by angiotensin-
convertingenzyme <ACE) inhibitors induces blockade of the
RAS in antihypertensive therapy. However, the lack of
speci®city of ACE inhibitors, havingthe adverse effects,
such as dry cough and angioedema, provided a major reason
for developingalternative therapy.
Although saralasin <Sar1-Ala8-AngII) was the ®rst spe-
ci®c peptide antagonist of AII and used as pharmacological
tools, the peptide has limited therapeutic value of the poor
oral bioavailability and short duration of action. Many
pharmaceutical industries have focused on ®ndinga more
speci®c way to block the RAS. Amongthem, nonpeptide AII
antagonists were an attractive means, lacking the disadvan-
tages of the peptide AII receptor antagonists. Most of them
contain a nitrogen heterocycle linked to a biphenyltetrazole
by a methylene spacer, as in losartan <Dup-753) [2] and
candesartan cilexetil <TCV-116) [3].
2. Synthesis of GA 0113
The key intermediate carboxyphenyl substituted quino-
line <3) was synthesized by the reaction of 5-methylisatin <1)
with 2-acetylbenzoic acid followed by selective decarbox-
ylation of the dicarboxylic acid thus produced <2) in the
presence of catalytic amount of H2SO4 in quinoline
<Scheme 1). After methyl esteri®cation and benzylic bro-
mination, an N-alkylation reaction with imidazopyridine
derivative <4) followed by hydrolysis gave the carboxyphe-
nyl-substituted quinoline GA 0056, which possessed anti-
hypertensive activity. Curtius rearrangement methodology
was then employed [using<PhO) 2P<O)N3-Et3N-t-BuOH] to
convert the carboxyl group to amino <CO2H ! CON3 !
There are some reports on the introduction of per¯uor-
oalkyl substituents in nonpeptide AII receptor antagonists
* Correspondingauthor. Tel.: 81-45-374-8799; fax: ‡81-45-374-8872.
E-mail address: ymoriz@agc.co.jp <Y. Morizawa).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 < 0 1 ) 0 0 3 8 3 - 9

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Y. Morizawa et al. / Journal of Fluorine Chemistry 109 82001) 83±86
Scheme 1.
NˆCˆO ! NHCO2But ! NH2); however, the aniline
derivative was obtained only in low yield <2% based on
1), even after improvingthe reaction conditions. Finally, the
quinolinylaniline was transformed into the desired tri¯amide
GA 0113, 6-{<2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b]pyr-
idin-3-yl)methyl}-2-[2-tri¯uoromethanesulfonamido)phe-
nyl]quinoline, by treatment with <CF3SO2)2O.
After several attempts to develop a satisfactory synthetic
method for producingbulk quantities of the quinolinylani-
line precursor of GA 0113, for example, unsuccessful
decarboxylation of the nitrophenyl analogue of compound
2 or a modi®ed Skraup reaction with 4-methylaniline and 3-
<2-nitrophenyl)acrolein, we have found a practical process
through the application of Conrad±Limpach's method
<Scheme 2).
Ringconstruction was accomplished by the reaction of 6
with p-toluidine, followed by treatment of 7 with polypho-
sphoric acid, then phosphorous oxychloride to give nitro-
phenylquinoline 8 in a fairly good yield. After N-alkylation
accordingto the transformation of 3 to GA 0056 <Scheme 1),
chloro-nitro compound 9 was reduced and the resulting
aniline converted to GA 0113. The overall yield of GA
0113 from 5 was 10%.
3. Results and discussion
3.1. Biological data
Pharmacological pro®les of GA 0113 are as follows [8]: a
bindingassay for AT and AT2 receptors was performed
The key 2-nitrophenyl ketone <6) was synthesized from 2-
nitrobenzoyl chloride<5)anddiethylmalonateinthepresence
of magnesium ethoxide, and successive decarboxylation.
1
usingcommercially-available membrane fractions expres-
singeither human AT or AT2. GA 0113 and CV-11974
1
Scheme 2.

Y. Morizawa et al. / Journal of Fluorine Chemistry 109 82001) 83±86
85
Fig. 2. Effect of oral administration of GA 0113 on systolic blood pressure
<A) and heart rate <B) in renal artery ligated hypertensive rats.
Fig. 1. Effects of GA 0113, CV-11974, and PD 123319 on specific binding
of ‰125IŠ-Sar1, Ile8-AngII to human AT receptors <A) and AT2 receptors
1
<B).
takinginto consideration that the p Ka <5 to 6) of arylte-
trazole is similar to that <4.45) of PhNHSO2CF3 [10], and a
unique quinolinyl group.
<an AT1 antagonist and a metabolite of TCV-116) displaced
the speci®c bindingof ‰125IŠ-Sar1, Ile8-AngII to bindingsites
in AT1 in a concentration-dependent manner <Fig. 1), and the
IC50 values were 1:1 Â 10À8 and 1:3 Â 10À7 mol/l, respec-
tively. In contrast, speci®c bindingof ‰125IŠ-Sar1, Ile8-AngII
3.2. MOPAC calculation
MOPACTM PM3 calculation of anions PhNSO2R
<R=CH3, CH2F, CHF2, CF3) in water <e ˆ 78:4) using
COSMO method optimized by EF indicated that the
bond-lengths of N±S increase gradually from 1.75 <CH3)
to bindingsites in AT was displaced by PD 123319, a
2
Ê
to 2.02 A <CF3) and the dipole moments of their anion are
selective AT2 antagonist, but not by GA 0113.
Antihypertensive effects in renal artery ligated hyperten-
sive rats <RALHR) was examined with male Wister rats.
Administration of GA 0113 <0.01±1 mg/kg) reduced systolic
blood pressure <SBP) in a dose-related manner with ED25 of
0.015 mg/kg, and at dose 0.1 mg/kg or more, SBP was
reduced for more than 24 h without affectingheart rate
<HR) signi®cantly <Fig. 2). Pharmacokinetic examination
revealed that GA 0113 has longer T1/2 <12.2 h) and much
better bioavailability <BA) <94%), whereas the T1/2 and BA
of TCV-116 have been reported to be 3.8 h and 19±28%,
respectively [9]. The high BA might attribute to the replace-
ment of the tetrazole group with the more lipophilic and
metabolically more stable acidic isostere, tri¯amide group,
dramatically decreased from 14.3 <CH3) to 9.7 D <CF3).
Moreover, we have found that AM1 Hamiltonian is not
suitable for such anions because the C±N±S bond angle
increased from 154.28<CH3) to 176.08<CF3).
4. Conclusion
Although GA 0113 is not structurally related to TCV-116
and other AT1 receptor antagonists bearing a biphenylte-
trazole moiety, it may become a potent agent for the treat-
ment of hypertension and other Angiotensin II-related
cardiovascular diseases.

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Y. Morizawa et al. / Journal of Fluorine Chemistry 109 82001) 83±86
Kleemann, J.P. Vevert, J.C. Vincent, A. Wagner, J. Zhang, J. Med.
Acknowledgements
Chem. 38 <1995) 2357.
[5] D.J. Carini, A.T. Chiu, P.C. Wong, A.L. Johnson, R.R. Wexler,
P.B.M.W.M. Timmermons, Bioorg. Med. Chem. Lett. 3 <1993) 895.
[6] M.D. Dowle, D.B. Judd, D. Middlemiss, D.I.C. Scopes, B.C. Ross,
M. Pass, E. Tranquillini, T.I. Jack, J.E. Hobson, T.A. Panchal, P.G.
Stuart, G.M. Drew, M.J. Robertson, A. Hilditch, K.L. Clark, A.
Travers, A.A.E. Hunt, G.R. Manchee, D.G. Walker, P.J. Eddershaw,
M. Donnelly, M.K. Bayliss, Bioorg. Med. Chem. Lett. 3 <1993) 2047.
[7] W.T. Ashton, L.L. Chang, K.L. Flanagan, S.M. Hutchins, E.M.
Naylor, P.K. Chakravarty, A.A. Patchett, W.J. Greenlee, T.B. Chen,
K.A. Faust, R.L. Chang, V.J. Lotti, G.J. Zingaro, T.W. Schorn, P.K.S.
Siegl, S.D. Kivlighn, J. Med. Chem. 27 <1994) 2808.
We thank Mr. Yoshihisa Inoue, DrugDiscovery Labora-
tories, Pharmaceutical Research Division, WelFide Cor-
poration for the MOPAC calculations and discussion.
References
[1] R.R. Wexler, W.J. Greenlee, J.D. Irvin, M.R. Goldberg, K.
Prendergast, R.D. Smith, P.B.M.W.M. Timmermans, J. Med. Chem.
39 <1996) 625.
[8] H. Ebisu, M. Nishikawa, M. Tanaka, T. Okazoe, Y. Morizawa, H.
Shinyama, N. Nakamura, J. Cardiovasc. Pharmacol. 34 <1999) 526.
[9] T. Kondo, K. Hagihara, Y. Kato, et al., Jpn. Pharmacol. Ther. 24
<1996) S-915.
[2] J.V. Duncia, D.J. Carini, A.T. Chiu, M.E. Pierce, W.A. Piece, R.D.
Smith, G.J. Wells, P.C. Wong, R.R. Wexler, A.L. Johnson,
P.B.M.W.M. Timmermans, Drugs Future 17 <1992) 326.
[3] K. Kubo, Y. Kohara, Y. Yoshimura, Y. Inada, Y. Shibouta, Y.
Furukawa, K. Nishikawa, T. Naka, J. Med. Chem. 36 <1993) 2343.
[4] P. Deprez, J. Guillaume, R. Becker, A. Corbier, S. Didierlaurent, M.
Fortin, D. Frechet, G. Hamon, B. Heckmann, H. Heitsch, H.W.
[10] J.V. Duncia, A.T. Chiu, D.J. Carini, G.B. Bregory, A.L. Johnson,
W.A. Price, G.J. Wells, P.C. Wong, J.C. Calabrese, P.M.W.M.
Timmermans, J. Med. Chem. 33 <1990) 1312.