Studies on disease-modifying antirheumatic drugs: Synthesis of novel quinoline and quinazoline derivatives and their anti-inflammatory effect

Article abstract of DOI:10.1021/jm9509408

In the course of our study aimed at developing new types of DMARDs (disease-modifying antirheumatic drugs), we found that quinoline derivative 1a had a potent anti-inflammatory effect in an adjuvant arthritis (AA) rat model, starting from the potent bone resorption inhibitors justicidins as the lead compounds. Further modification of 1a was performed, and various quinoline and quinazoline derivatives having a heteroaryl moiety on the alkyl side chain at the 2-position of the skeleton were prepared. These compounds were evaluated for antiinflammatory effects using the AA rat model. Most of these compounds, especially those having an imidazole or a triazole moiety on the 2-alkyl chain, exhibited a potent effect. Among the compounds synthesized, ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1- yl-methyl)quinoline-3-carboxylate (12d), having an ED₅₀ value of 2.6 mg/kg/day (anti-inflammatory effect in an AA rat model, po), was selected as a candidate for further investigation. In vitro, 12d inhibited mitogen- induced proliferation at 10^-7-10^-5 M but not prostaglandin E₂ production at 10^-5 M. Moreover, 12d preferentially inhibited the IFN-γ production by Th1-type clones over the IL-4 production by Th2-type clones. This preferential suppression of Th1 cytokine production is considered the essential immunomodulating action of 12d for the present. Synthesis and structure-activity relationships for this novel series of quinoline and quinazoline derivatives are detailed.

Full text of DOI:10.1021/jm9509408

5176
J . Med. Chem. 1996, 39, 5176-5182
Stu d ies on Disea se-Mod ifyin g An tir h eu m a tic Dr u gs: Syn th esis of Novel
Qu in olin e a n d Qu in a zolin e Der iva tives a n d Th eir An ti-in fla m m a tor y Effect1
Atsuo Baba,† Noriaki Kawamura,‡ Haruhiko Makino,† Yoshikazu Ohta,† Shigehisa Taketomi,† and
Takashi Sohda*,†
Pharmaceutical Research Division and Discovery Research Division, Takeda Chemical Industries, Ltd.,
17-85 J usohonmachi 2-chome, Yodogawa-ku, Osaka 532, J apan
Received December 27, 1995X
In the course of our study aimed at developing new types of DMARDs (disease-modifying
antirheumatic drugs), we found that quinoline derivative 1a had a potent anti-inflammatory
effect in an adjuvant arthritis (AA) rat model, starting from the potent bone resorption inhibitors
justicidins as the lead compounds. Further modification of 1a was performed, and various
quinoline and quinazoline derivatives having a heteroaryl moiety on the alkyl side chain at
the 2-position of the skeleton were prepared. These compounds were evaluated for anti-
inflammatory effects using the AA rat model. Most of these compounds, especially those having
an imidazole or a triazole moiety on the 2-alkyl chain, exhibited a potent effect. Among the
compounds synthesized, ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-yl-
methyl)quinoline-3-carboxylate (12d ), having an ED50 value of 2.6 mg/kg/day (anti-inflammatory
effect in an AA rat model, po), was selected as a candidate for further investigation. In vitro,
12d inhibited mitogen-induced proliferation at 10-7-10-5 M but not prostaglandin E2 production
at 10-5 M. Moreover, 12d preferentially inhibited the IFN-γ production by Th1-type clones
over the IL-4 production by Th2-type clones. This preferential suppression of Th1 cytokine
production is considered the essential immunomodulating action of 12d for the present.
Synthesis and structure-activity relationships for this novel series of quinoline and quinazoline
derivatives are detailed.
Ch a r t 1
In tr od u ction
Rheumatoid arthritis (RA) is a serious, chronic, and
systemic disease characterized by inflammation and
progressive joint destruction.2 Nonsteroidal anti-in-
flammatory drugs (NSAIDs),3 the primary treatment for
RA, provide only symptomatic relief for acute inflam-
mation. Recently, as it has become clear that RA is a
type of autoimmune disease,4 disease-modifying anti-
rheumatic drugs (DMARDs), which have a selective and
direct action on the abnormal immune system, have
attracted a great deal of attention as potentially effec-
tive therapies for RA.5
In our study aimed at developing new types of
DMARDs, particular interest was directed toward bone
resorption inhibitors, since the final stage of RA is bone
destruction and several cytokines such as interleukin-
1â (IL-1â) play an important role in both RA and bone
metabolism.6 Thus, we selected the potent bone resorp-
tion inhibitors justicidins (Chart 1) as the lead com-
pounds. Among compounds modified based on the
justicidin structure,7 compound 1a , in which the naph-
thalene ring has been replaced by a quinoline ring and
a 2-(1-methylimidazolyl) moiety has been introduced at
the 2-methyl position generated by ring opening of the
lactone, was found to have a potent anti-inflammatory
effect in rats with adjuvant arthritis (AA). Further
modification of 1a was performed, and various quino-
line-3-carboxylate derivatives and quinazoline deriva-
tives possessing a heteroaryl moiety on the alkyl chain
at the 2-position of the skeleton were synthesized. In
this article, we report the synthesis of this novel series
of quinoline and quinazoline derivatives and structure-
activity relationships (SAR) with regard to the anti-
inflammatory effect in the rats with adjuvant arthritis
are discussed.
Ch em istr y
The 2-[[(heteroaryl)thio]methyl]quinoline derivatives
1 and 2-[[(heteroaryl)thio]methyl]quinazoline deriva-
tives 2 listed in Table 1 were synthesized by coupling
of the 2-(chloromethyl)quinolines 3 or 2-(chloromethyl)-
quinazolines 4 with (heteroaryl)thiols in the presence
of K2CO3. Subsequent mCPBA oxidation of 1 gave
sulfoxides 5 or sulfones 6 (method A, Scheme 1).
2-[(Heteroaryl)ethyl]quinolines 9 and 2-[(heteroaryl)-
ethyl]quinazolines 10 were prepared by method B
involving the Wittig reaction as a key step. The
phosphonium salts 7 and 8 obtained from 3 and 4 were
treated with NaOEt, and subsequent reaction with
(heteroaryl)aldehydes gave 2-vinyl derivatives as a
* Correspondence should be addressed to this author. Phone: +81-
6-300-6117. Fax: +81-6-300-6306.
† Pharmaceutical Research Division.
‡ Discovery Research Division.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
S0022-2623(95)00940-X CCC: $12.00 © 1996 American Chemical Society

Disease-Modifying Antirheumatic Drugs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5177
Sch em e 1a
a
(a) Heteroaryl-SH, K2CO3; (b) mCPBA (1.1 equiv); (c) mCPBA (2.2 equiv); (d) PPh3; (e) NaOEt then heteroaryl-CHO; (f) H2, Pd-C.
Sch em e 2
Sch em e 3a
mixture of E and Z isomers, which was hydrogenated
without further separation to provide 9 and 10.
Compounds 12 and 13 having a triazolyl or an
imidazolyl moiety on the 2-alkyl chain were prepared
according to the methods shown in Scheme 2. Coupling
of 3, 4, or 11 with 1H-1,2,4-triazole or imidazole
provided the corresponding 1-azolyl derivatives 12 (n
) 1 or 2) and 13 (n ) 1) (method C). The extended-
chain analogues 12 (n ) 3 or 4) were synthesized by
Friedla¨nder reaction8 of 2-aminobenzophenones 149
with â-keto esters 15 (method D).10 The requisite â-keto
esters 15 for method D were obtained following the
procedure reported by Masamune et al.,11 starting from
ω-bromo carboxylic acids 16, in five steps (Scheme 3).
a
(a) (COCl)2, DMF; (b) benzyl alcohol, Et3N; (c) imidazole or
triazole, NaH; (d) H2, Pd-C; (e) N,N′-carbonyldiimidazole then
Mg(OCOCH2COOEt)2.
derived from 14. 18 was converted to 2-(bromoethyl)-
quinolines 11 in the usual way (method F). The
2-(chloromethyl)quinazolines 4 were prepared by cy-
clization of 14 with chloroacetonitrile in the presence
of AlCl3 (method G).
Resu lts a n d Discu ssion
Syntheses of the desired 2-haloalkyl derivatives for
methods A-C above are summarized in Scheme 4.
2-(Chloromethyl)quinolines 3 were synthesized by Fried-
la¨nder reaction of 14 with the corresponding 4-chloro-
acetoacetic acid esters under acidic conditions (method
E). In an analogous fashion, diester derivatives 18 were
The structures and physical data of the quinoline and
quinazoline derivatives synthesized are shown in Tables
1 and 2. Anti-inflammatory effects of these derivatives
are listed in Table 3, and the activity is presented in
terms of the plantar edema inhibitory rate (%) (see
Biological Procedures).

5178 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Baba et al.
Sch em e 4a
In conclusion, modification of justicidins revealed that
quinoline and quinazoline derivatives having an azolyl
moiety on the side chain at the 2-position have a potent
anti-inflammatory effect. Extremely potent activities
were attained in a series of 2-(1-imidazolyl- and 1-tri-
azolylmethyl)quinolines 12. Among these compounds,
compound 12d having an ED50 value of 2.6 mg/kg/day
(anti-inflammatory effect in an AA rat model) was
selected as a candidate for further investigation. Phar-
macological evaluation revealed that 12d has the profile
of an immunomodulator.12 Since 12d potently inhibited
paw swelling in AA but not carrageenin-induced paw
swelling at 50 mg/kg, its action is not like that of
NSAIDs. Compound 12d suppressed the type IV al-
lergic response (25 mg/kg/day, po) but had no effect on
the type III allergic response in mice. In vitro, 12d
a
(a) ClCH2COCH2COOR3 (R3 ) Me, Et), concentrated H2SO4/
inhibited mitogen-induced proliferation at 10-7-10-5
M
AcOH; (b) CO(CH2COOEt)2, concentrated H2SO4/AcOH; (c) LiAlH4;
(d) PBr3; (e) ClCH2CN, AlCl3.
but not PGE2 production at 10-5 M. To investigate the
mechanism of 12d in more detail, we established Th1
(allo-reactive) and Th2 (ovalbumine (OVA)-reactive) T
cell lines and studied the effect of 12d on their cytokine
production. Compound 12d suppressed Th1 cytokines
(IL-2 and IFN-γ) but not Th2 cytokine (IL-4) in both
cell lines. Moreover, 12d preferentially inhibited IFN-γ
production by Th1-type clones over IL-4 production by
Th2-type clones. From these data, we consider that 12d
is an immunomodulator with the potential to control
bone and cartilage destruction but devoid of any effect
on prostaglandin synthesis inhibitory effect, and we
expect it to be useful as a new type of DMARD. These
quinoline and quinazoline derivatives are possible lead
compounds for the development of potent antiosteoporot-
ic agents. The SAR for the bone resorption inhibitory
effect of these novel quinoline and quinazoline deriva-
tives will be published elsewhere.14
Our search for the discovery of a new type of DMARDs
started with chemical modification of justicidins (Chart
1), and 4-phenylquinoline-3-carboxylate derivative 1a
was the first compound found with the desired biological
activity. Thus, further modification of 1a was per-
formed.
First, the effect of a heteroaryl moiety on the side
chain at the 2-position was examined. Compounds
1b-d possessing an imidazole or a triazole group
showed potent activity.
The effect of adding substituents to the quinoline ring
(R1) and the pendent phenyl ring (R2) at the 4-position
was studied with compounds 1a ,f-n . Generally, potent
anti-inflammatory activity was observed with com-
pounds having 6,7-dialkoxy (1a ,f,k ,l) for R1 and 3,4-
dialkoxy (1a ,f,k ,l) for R2. Compounds lacking the
alkoxy moiety had reduced activity (1a vs 1j,n ). Con-
cerning substituents R2, compounds possessing 4-meth-
oxy (1g) or 4-methyl (1h ) also showed potent activity.
Considering the structure-activity relationships men-
tioned above, we focused our further synthetic efforts
on the preparation of various quinoline-3-carboxylate
and quinazoline derivatives bearing 6,7-dimethoxy and
4-(3,4-dimethoxyphenyl) moieties.
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Yanagim-
oto micromelting point apparatus and are uncorrected. El-
emental analysis (C, H, and N) was carried out by the
Analytical Department of Takeda Chemical Industries, Ltd.
1H NMR spectra of deuteriochloroform or DMSO-d6 solutions
(internal standard TMS, δ 0) were recorded on a Varian
Gemini-200 spectrometer. Infrared spectra were recorded on
a Hitachi IR-215 spectrometer. All compounds exhibited 1H
NMR, IR, and analytical data consistent with the proposed
structures. Column chromatography was done with E. Merck
silica gel 60 (0.063-0.200 mm).
Meth od A: Gen er a l P r oced u r e for 2-[[(Heter oa r yl)-
th io]m eth yl]qu in olin es 1 a n d 2-[[(Heter oa r yl)th io]m eth -
yl]qu in a zolin es 2. Eth yl 4-(3,4-Dim eth oxyp h en yl)-6,7-
d im e t h o xy -2-[[(1-m e t h ylim id a zol-2-yl)t h io ]m e t h y l]-
qu in olin e-3-ca r boxyla te (1a ). A mixture of ethyl 2-(chlo-
romethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-
carboxylate (22.2 g, 49.8 mmol), 2-mercapto-1-methylimidazole
(6.2 g, 54.8 mmol), K2CO3 (7.6 g, 54.8 mmol), and DMF (280
mL) was stirred at room temperature for 3 h, poured into H2O
(500 mL), and extracted with AcOEt. The extract was washed
with H2O and brine, dried over MgSO4, and concentrated in
vacuo. The residue was chromatographed on SiO2 (300 g) with
CHCl3-AcOEt (7:3) to give crystals. Recrystallization from
acetone-Et2O gave 1a as colorless prisms (20.0 g, 77%): mp
149-150 °C; 1H NMR (CDCl3) δ 0.99 (3H, t, J ) 7.2 Hz), 3.47
(3H, s), 3.79 (3H, s), 3.87 (3H, s), 3.97 (3H, s), 4.03 (2H, q, J )
7.2 Hz), 4.04 (3H, s), 4.61 (2H, s), 6.87-7.01 (5H, m), 7.08 (1H,
d, J ) 1.2 Hz), 7.38 (1H, s). Anal. (C27H29N3O6S), C,H,N.
4-(3,4-Dim et h oxyp h en yl)-6,7-d im et h oxy-2-[[(1-m et h -
ylim id a zol-2-yl)th io]m eth yl]qu in a zolin e (2a ). The title
compound was prepared according to the method described for
1a : mp 184-185 °C; 1H NMR (CDCl3) δ 3.50 (3H, s), 3.90 (3H,
S-Oxide compounds 5a and 6a , obtained by oxidation
of 1a , exhibited activities either stronger than or
comparable to that of the parent compound. These
findings suggest the possibility that sulfoxide 5a and
sulfone 6a are active metabolites of 1a .
Replacement of the sulfide moiety of 1a with a
methylene enhanced the activity (9a vs 1a ), showing
that a linker between the quinoline and the imidazole
rings is an important factor. A similar effect was also
observed for the quinazoline derivatives (10a vs 2a ).
On the basis of these findings, compounds 12 and 13
(Table 2), in which an alkyl side chain is connected to
the azole nitrogen, were synthesized. Among these
compounds, 12a -d possessing methylene as the linker
exhibited remarkably potent activity. However, exten-
sion of the alkyl side chain from one to three carbons
resulted in a decrease in potency (12e vs 12d ).
Since our search for a new type of DMARDs started
with chemical modification of a bone resorption inhibitor
as described above, the bone resorption inhibitory effect
was also evaluated. Some of these compounds show
potent bone resorption inhibitory activity and are shown
in Table 4.

Disease-Modifying Antirheumatic Drugs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5179
Ta ble 1. Physical Data and Yield of Quinolines 1, 5, 6, and 9 and Quinazolines 2 and 10
compd
R1
R2
G
R4
Y
Z
yielda (%)
mp (°C)
formula
anal.b
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
2a
5a
6a
9a
10a
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(EtO)2
6,7-O(CH2)2O-
6-MeO
3,4-(MeO)2
3,4-(MeO)2
3,4-(MeO)2
3,4-(MeO)2
3,4-(MeO)2
3,4-OCH2O
4-MeO
4-Me
4-Cl
H
3,4-(MeO)2
3,4-(MeO)2
4-MeO
3,4-(MeO)2
3,4-(MeO)2
3,4-(MeO)2
3,4-(MeO)2
3,4-(MeO)2
3,4-(MeO)2
C-COOEt
C-COOEt
C-COOEt
C-COOEt
C-COOMe
C-COOEt
C-COOEt
C-COOEt
C-COOEt
C-COOEt
C-COOEt
C-COOEt
C-COOEt
C-COOEt
N
Me
Me
H
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
CH
N
77
77
65
78
69
70
72
46
71
60
74
57
67
95
81
58c
58c
75
72
149-150
147-148
111-112
157-158
159-160
176-177
123-124
134-135
132-133
101-102
132-133
120-121
110-111
141-142
184-185
193-194
183-184
147-148
170-171
C27H29N3O6S
C26H28N4O6S
C26H27N3O6S
C28H31N3O6S
C26H27N3O6S
C26H25N3O6S
C26H27N3O5S
C26H27N3O4S
C25H24ClN3O4S
C25H25N3O4S
C29H33N3O6S
C27H27N3O6S
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
C25H25N3O4S
H
C25H25N3O4S
C23H24N4O4S
C27H29N3O7S
C27H29N3O8S
C28H31N3O6
C24H26N4O4
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
6,7-(MeO)2
C-COOEt
C-COOEt
C-COOEt
N
S(O)
S(O)2
CH2
CH2
a
b
Yield from 3 or 4. All compounds gave satisfactory results ((0.4%). c Yield from 1a .
Ta ble 2. Physical Data and Yield of Quinolines 12 and
Quinazolines 13
Meth od B: Gen er a l P r oced u r e for 2-[(Heter oa r yl)-
eth yl]qu in olin es 9 a n d 2-[(Heter oa r yl)eth yl]qu in a zo-
lin es 10. Eth yl 4-(3,4-Dim eth oxyp h en yl)-6,7-d im eth oxy-
2-[2-(1-m e t h y lim id a zo l-2-y l)e t h y l]q u in o lin e -3-c a r -
boxyla te (9a ). A mixture of ethyl 2-(chloromethyl)-4-(3,4-
dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (30 g,
67.3 mmol), PPh3 (17.6 g, 67.3 mmol), and toluene (200 mL)
was stirred under reflux for 2 h. After cooling to room
temperature, the precipitated crystals were collected by filtra-
tion and washed with Et2O to afford [4-(3,4-dimethoxyphenyl)-
6,7-dimethoxy-3-(ethoxycarbonyl)quinolin-2-yl]methyltriphe-
nylphosphonium chloride (40.0 g, 84%): mp 200-202 °C dec;
1H NMR (DMSO-d6) δ 0.83 (3H, t, J ) 7.0 Hz), 3.67 (3H, s),
3.74 (3H, s), 3.83 (6H, s), 3.99 (2H, q, J ) 7.0 Hz), 5.65 (2H, d,
J ) 14.8 Hz), 6.70 (1H, s), 6.79-6.90 (3H, m), 7.08-7.24 (2H,
m), 7.65-7.94 (14H, m).
[4-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-3-(ethoxycarbonyl)-
quinolin-2-yl]methyltriphenylphosphonium chloride (17.4 g,
24.0 mmol) was added to a stirred solution of NaOEt (prepared
from Na (0.62 g, 26.7 mmol) and EtOH (150 mL)) at ambient
temperature. After stirring for 10 min, a solution of 2-formyl-
1-methylimidazole (3.7 g, 33.9 mmol) in EtOH (20 mL) was
added dropwise. The whole was stirred at room temperature
for 3 h, poured into H2O (500 mL), and extracted with AcOEt.
The extract was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was chro-
matographed on SiO2 (200 g) with CHCl3-MeOH (100:1) to
give a mixture of (E)- and (Z)-ethyl 4-(3,4-dimethoxyphenyl)-
6,7-dimethoxy-[2-(1-methylimidazol-2-yl)vinyl]quinoline-3-car-
boxylate (ca. 10.9 g). Almost the same scale reaction was
repeated, and the total yield was 25.5 g.
yielda
(%)
compd
G
Z
R
n
mp (°C)
formula
anal.b
12a
C-COOEt CH
H
1
1
1
1
3
1
1
75
81
74
62
208-209 C26H27N3O6 C,H,N
177-178 C27H29N3O6 C,H,N
163-165 C28H31N3O6 C,H,N
176-177 C25H26N4O6 C,H,N
12b C-COOEt CH Me
12c C-COOEt CH Et
12d C-COOEt
12e
13a
13b
N
N
H
H
C-COOEt
40c 141-142 C27H30N4O6 C,H,N
N
N
CH Me
N
55
58
223-224 C23H24N4O4 C,H,N
206-207 C21H21N5O4 C,H,N
H
a
b
Yield from 3 or 4. All compounds gave satisfactory results
((0.4%). c Yield from 14.
s), 3.97 (3H, s), 3.98 (3H, s), 4.06 (3H, s), 4.59 (2H, s), 6.90
(1H, s), 6.95-7.13 (2H, m), 7.23-7.43 (4H, m). Anal.
(C23H24N4O4S) C,H,N.
Eth yl 4-(3,4-Dim eth oxyp h en yl)-6,7-d im eth oxy-2-[[(1-
m et h ylim id a zol-2-yl)su lfin yl]m et h yl]q u in olin e-3-ca r b -
oxyla te (5a ). mCPBA (85%, 1.28 g, 6.30 mmol) was added
portionwise to a solution of 1a (3.0 g, 5.73 mmol) in CH2Cl2
(75 mL) with ice cooling, and the whole was stirred at ambient
temperature for 2.5 h. The mixture was washed successively
with 5% aqueous NaHSO3, saturated aqueous NaHCO3, and
H2O, dried over MgSO4, and concentrated in vacuo. The
residue was chromatographed on SiO2 (100 g) with AcOEt-
MeOH (10:1) to give crystals. Recrystallization from acetone-
Et2O gave 5a as colorless prisms (1.8 g, 58%): mp 193-194
A mixture of (E)- and (Z)-ethyl 4-(3,4-dimethoxyphenyl)-6,7-
dimethoxy-[2-(1-methylimidazol-2-yl)vinyl]quinoline-3-carb-
oxylate obtained above (ca. 25.5 g), 5% Pd-C (6 g), and THF-
EtOH (1:1, 600 mL) was hydrogenated at room temperature
under atmospheric pressure. The catalyst was filtered off, and
the filtrate was concentrated in vacuo to give crystals. Re-
crystallization from EtOH gave 9a as colorless prisms (19.2
g, 75%): mp 147-148 °C; 1H NMR (CDCl3) δ 0.98 (3H, t, J )
7.2 Hz), 3.18-3.33 (2H, m), 3.35-3.52 (2H, m), 3.60 (3H, s),
3.80 (3H, s), 3.87 (3H, s), 3.96 (3H, s), 4.05 (3H, s), 4.06 (2H,
q, J ) 7.2 Hz), 6.80 (1H, d, J ) 1.4 Hz), 6.87-7.01 (5H, m),
7.42 (1H, s). Anal. (C28H31N3O6) C,H,N.
1
°C; H NMR (CDCl3) δ 0.96 (3H, t, J ) 7.2 Hz), 3.79 (3H, s),
3.87 (3H, s), 3.94 (3H, s), 3.97 (3H, s), 4.05 (3H, s), 4.06 (2H,
q, J ) 7.2 Hz), 4.99-5.19 (2H, m), 6.84-6.99 (5H, m), 7.15
(1H, d, J ) 1.2 Hz), 7.38 (1H, s). Anal. (C27H29N3O7S) C,H,N.

5180 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Baba et al.
Ta ble 3. Anti-inflammatory Effect of Quinolines and Quinazolines
paw vola (% inhib)
ED50 (mg/kg)
compd
dose (mg/kg)
paw vola (% inhib)
ED50 (mg/kg)
b
b
compd
dose (mg/kg)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
50
50
50
50
50
50
50
50
50
50
50
50
50
50
60** c
66***
60**
51*
67**
63**
64*
67***
41**
31
59**
56**
45*
25.0
11.6
2a
5a
6a
9a
10a
12a
12b
12c
12d
50
12.5
50
50
50
12.5
12.5
12.5
12.5
12.5
12.5
12.5
50
<50
73**
56**
75***
71**
70**
55**
65**
65**
<50
<50
<50
10
6.5
14.7
7.7
9.1
2.6
12e
13a
13b
33**
justicidin A
a
The test compounds were given orally for 14 days after adjuvant injection into the rat’s right hind paw. Each volume was obtained
b
by comparison between the left paw volume in the arthritic group and that in the control group (see Biological Procedures). Effective
dose (mg/kg) of 50% inhibition, estimated from dose-response curve at three or four doses. c Statistically significant at *p <0.05, **p <
0.01, and ***p < 0.001, by Student’s t-test.
Ta ble 4. Bone Resorption Inhibitory Effect of 1a ,e,l,m and
12d
3,4,4′,5-tetramethoxybenzophenone (4.0 g, 12.7 mmol), ethyl
3-oxo-6-(1,2,4-triazol-1-yl)hexanoate (2.6 g, 11.54 mmol), con-
centrated H2SO4 (0.37 g, 3.75 mmol), and acetic acid (40 mL)
was stirred at 100 °C for 2 h and concentrated in vacuo. The
residue was alkalinized with 2 N aqueous NaOH and extracted
with CHCl3. The extract was washed with H2O and brine,
dried over MgSO4, and concentrated in vacuo. The residue
was chromatographed on SiO2 (60 g) with CHCl3-MeOH (40:
1) to give crystals. Recrystallization from EtOH gave 12e as
colorless prisms (2.5 g, 40%): mp 141-142 °C; 1H NMR
(CDCl3) δ 0.99 (3H, t, J ) 7.2 Hz), 2.49 (2H, quintet, J ) 7.0
Hz), 2.97 (2H, t, J ) 7.0 Hz), 3.80 (3H, s), 3.88 (3H, s), 3.97
(3H, s), 4.04 (2H, q, J ) 7.2 Hz), 4.07 (3H, s), 4.34 (2H, t, J )
7.0 Hz), 6.87-7.01 (4H, m), 7.40 (1H, s), 7.94 (1H, s), 8.20 (1H,
s). Anal. (C27H30N4O6) C,H,N.
compd
conctn (µM)
45Ca releasea (% of control)
1a
1e
1l
1m
30
10
10
10
30
25
25
57*** b
46***
66***
66**
59**
48**
12d
justicidin A
justicidin B
47**
a
Bone resorption inhibitory effects were evaluated by Raisz’s
b
method (see Biological Procedures). Statistically significant at
**p < 0.01 and ***p < 0.001, by Student’s t-test.
4-(3,4-Dim eth oxyp h en yl)-6,7-d im eth oxy-2-[2-(1-m eth -
ylim id a zol-2-yl)eth yl]qu in a zolin e (10a ). The title com-
pound was prepared according to the method described for
Gen er a l P r oced u r e for ω-(1-Azolyl) â-Keto Ester s 15.
Eth yl 3-oxo-6-(1,2,4-tr ia zol-1-yl)h exa n oa te. Oxalyl chlo-
ride (2.9 g, 23.3 mmol) was added dropwise to a stirred solution
of 4-bromobutyric acid (3.0 g, 17.9 mmol) in THF (30 mL) with
ice cooling, and then DMF (2 drops) was added. The whole
was stirred at 0 °C for 1 h and concentrated in vacuo. The
residual acid chloride was dissolved in CH2Cl2 (10 mL). The
solution was added dropwise to a stirred mixture of benzyl
alcohol (2.9 g, 26.9 mmol), Et3N (3.6 g, 35.9 mmol), and CH2-
Cl2 (30 mL) with ice cooling. After stirring at 0 °C for 4 h, the
reaction mixture was poured into H2O (200 mL). The organic
layer separated was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was chromatographed on
SiO2 (60 g) with AcOEt-hexane (1:1) to give benzyl 4-bro-
mobutyrate as an oil (4.2 g, 91%).
A mixture of benzyl 4-bromobutyrate (72.6 g, 0.282 mol),
1H-1,2,4-triazole (21.4 g, 0.310 mol), K2CO3 (46.8 g, 0.339 mol),
and acetone (1000 mL) was stirred under reflux for 8 h. The
insoluble solid was filtered off, and the filtrate was concen-
trated in vacuo. The residue was chromatographed on SiO2
(700 g) with CHCl3-MeOH (15:1) to give benzyl 4-(1,2,4-
triazol-1-yl)butyrate as an oil (60.9 g, 88%).
1
9a : mp 170-171 °C; H NMR (CDCl3) δ 3.27-3.39 (2H, m),
3.53-3.65 (2H, m), 3.61 (3H, s), 3.91 (3H, s), 3.97 (3H, s), 3.99
(3H, s), 4.08 (3H, s), 6.79 (1H, d, J ) 1.2 Hz), 6.95 (1H, d, J )
1.2 Hz), 7.04 (1H, d, J ) 8.8 Hz), 7.30-7.42 (4H, m). Anal.
(C24H26N4O4) C,H,N.
Meth od C: Gen er a l P r oced u r e for 2-(1-Im id a zolyl- or
1-tr ia zolylm eth yl)qu in olin es 12 a n d 2-(1-Im id a zolyl- or
1-tr ia zolylm eth yl)qu in a zolin es 13. Eth yl 4-(3,4-Dim eth -
oxyp h en yl)-6,7-d im et h oxy-2-(1,2,4-t r ia zol-1-ylm et h yl)-
qu in olin e-3-ca r boxyla te (12d ). A mixture of 1H-1,2,4-
triazole (558 mg, 8.07 mmol) in DMF (30 mL) was treated with
NaH (60% in oil, 323 mg, 8.07 mmol) at ambient temperature
for 15 min, and then ethyl 2-(chloromethyl)-4-(3,4-dimeth-
oxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (3.0 g, 6.73
mmol) was added. The whole was stirred at 80 °C for 1 h,
poured into H2O (100 mL), and extracted with AcOEt. The
extract was washed with H2O and brine, dried over MgSO4,
and concentrated in vacuo. The residue was chromatographed
on SiO2 (40 g) with CHCl3-MeOH (40:1) to give crystals.
Recrystallization from AcOEt-hexane gave 12d as colorless
prisms (1.9 g, 62%): mp 176-177 °C; 1H NMR (CDCl3) δ 0.88
(3H, t, J ) 7.2 Hz), 3.80 (3H, s), 3.86 (3H, s), 3.95 (2H, q, J )
7.2 Hz), 3.97 (3H, s), 4.05 (3H, s), 5.74 (2H, s), 6.86-7.00 (4H,
m), 7.42 (1H, s), 7.94 (1H, s), 8.28 (1H, s). Anal. (C25H26N4O6)
C,H,N.
4-(3,4-Dim eth oxyph en yl)-6,7-dim eth oxy-2-[(2-m eth ylim -
id a zol-1-yl)m eth yl]qu in a zolin e (13a ). The title compound
was prepared according to the method described for 12d : mp
223-224 °C; 1H NMR (CDCl3) δ 2.52 (3H, s), 3.92 (3H, s), 3.95
(3H, s), 3.99 (3H, s), 4.07 (3H, s), 5.37 (2H, s), 6.95 (1H, d, J )
1.2 Hz), 7.03 (1H, d, J ) 8.0 Hz), 7.08 (1H, d, J ) 1.2 Hz),
7.28 (2H, s), 7.36 (1H, dd, J ) 8.0, 1.8 Hz), 7.42 (1H, s). Anal.
(C23H24N4O4) C,H,N.
Meth od D: Gen er a l P r oced u r e for 2-(1-Im id a zolyl- or
1-tr ia zolylp r op yl a n d -bu tyl)qu in olin es 12. Eth yl 4-(3,4-
Dim eth oxyp h en yl)-6,7-d im eth oxy-2-[3-(1,2,4-tr ia zol-1-yl)-
pr opyl]qu in olin e-3-car boxylate (12e). A mixture of 2-amino-
A mixture of benzyl 4-(1,2,4-triazol-1-yl)butyrate (60 g, 0.244
mol), 5% Pd-C (15 g), and EtOH (500 mL) was hydrogenated
at ambient temperature under atmospheric pressure. The
catalyst was filtered off, and the filtrate was concentrated in
vacuo to give crystals. Recrystallization from EtOH gave
4-(1,2,4-triazol-1-yl)butyric acid as colorless prisms (23.4 g,
1
61%): mp 137-138 °C; H NMR (CDCl3) δ 1.98 (2H, quintet,
J ) 6.8 Hz), 2.21 (2H, t, J ) 6.8 Hz), 4.20 (2H, t, J ) 6.8 Hz),
7.95 (1H, s), 8.50 (1H, s), 12.18 (1H, s). Anal. (C6H9N3O2)
C,H,N.
N,N′-Carbonyldiimidazole (6.9 g, 42.5 mmol) was added to
a stirred suspension of 4-(1,2,4-triazol-1-yl)butyric acid (6.0 g,
38.7 mmol) in THF (250 mL) at room temperature, and the
whole was stirred at the same temperature for 6 h. Mg-
(OCOCH2CO2Et)2 (12.2 g, 42.5 mmol) was added followed by
stirring for 15 h. The reaction mixture was concentrated in
vacuo, and the residue was dissolved in CH2Cl2 (200 mL). The

Disease-Modifying Antirheumatic Drugs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5181
solution was washed with saturated aqueous NH4Cl, H2O, and
brine, dried over MgSO4, and concentrated in vacuo. The
residue was chromatographed on SiO2 (45 g) with AcOEt-
MeOH (20:1) to give the title compound as an oil (2.6 g, 30%):
1H NMR (CDCl3) δ 1.28 (3H, t, J ) 7.2 Hz), 2.19 (2H, quintet,
J ) 6.6 Hz), 2.59 (2H, t, J ) 6.6 Hz), 3.43 (2H, s), 4.19 (2H, q,
J ) 7.2 Hz), 4.23 (2H, t, J ) 6.6 Hz), 7.94 (1H, s), 8.07 (1H, s);
into H2O and extracted with CHCl3. The extract was washed
with H2O and brine, dried over MgSO4, and concentrated in
vacuo. The residue was chromatographed on SiO2 (100 g) with
CHCl3-AcOEt (10:1) to give crystals. Recrystallization from
acetone gave the title compound as colorless prisms (4.9 g,
1
52%): mp 183-184 °C; H NMR (CDCl3) δ 3.93 (3H, s), 3.98
(3H, s), 3.99 (3H, s), 4.08 (3H, s), 4.91 (2H, s), 7.06 (1H, d, J )
8.8 Hz), 7.34-7.46 (4H m). Anal. (C19H19ClN2O4) C,H,N.
Biologica l P r oced u r es. 1. An ti-in fla m m a tor y Effect
in Ad ju va n t Ar th r itis.15 Male Lewis rats (7 weeks old;
Charles River J apan Inc.) (n ) 7) were sensitized by injecting
Freund’s complete adjuvant (a 0.5% suspension of killed
Mycobacterium tuberculosis (H37 RA, Difco) in liquid paraffin)
(0.05 mL) intradermally at a plantar site on the right hind
leg. A suspension of a test compound in 0.5% methylcellulose
was orally administered once a day for 14 days. The admin-
istration was started just before sensitization (day 0). The left
hind paw volume was measured just before sensitization (day
0) and on day 14, and the plantar edema inhibitory rate and
the body weight gain rate were determined in comparison with
the nonsensitized rat group. Effective dose to inhibit the rat’s
left hind paw swelling by 50% (ED50) was determined using
data from an experiment in which three or four different doses
were used. The doses were selected according to the potency
of compound. ED50 (mg/kg) was derived by linear regression
analysis of the data.
IR (neat) ν 1740, 1710 cm-1
.
Meth od E: Gen er a l P r oced u r e for Meth yl or Eth yl
2-(Ch lor om et h yl)q u in olin e-3-ca r b oxyla t es 3. E t h yl 2-
(Ch lor om e t h yl)-4-(3,4-d im e t h oxyp h e n yl)-6,7-d im e t h -
oxyqu in olin e-3-ca r boxyla te. A mixture of 2-amino-3,4,4′,5-
tetramethoxybenzophenone (30.0 g, 94.5 mmol), ethyl 4-chlo-
roacetoacetate (17.1 g, 0.104 mol), concentrated H2SO4 (1.5
mL), and acetic acid (300 mL) was stirred at 100 °C for 3 h
and concentrated in vacuo. The residue was alkalinized with
2 N aqueous NaOH and extracted with CHCl3. The extract
was washed with H2O and brine, dried over MgSO4, and
concentrated in vacuo. The residue was chromatographed on
SiO2 (350 g) with CHCl3-AcOEt (10:1) to give crystals.
Recrystallization from acetone-Et2O gave the title compound
1
as colorless prisms (22.2 g, 53%): mp 147-148 °C; H NMR
(CDCl3) δ 1.02 (3H, t, J ) 7.2 Hz), 3.81 (3H, s), 3.88 (3H, s),
3.98 (3H, s), 4.06 (3H, s), 4.09 (2H, q, J ) 7.2 Hz), 4.93 (1H, d,
J ) 11.2 Hz), 4.99 (1H, d, J ) 11.2 Hz), 6.91-7.02 (4H, m),
7.47 (1H, s). Anal. (C23H24ClNO6) C,H,N.
Meth od F : Gen er a l P r oced u r e for Eth yl 2-(2-Br om o-
et h yl)q u in olin e-3-ca r b oxyla t es 11. E t h yl 2-(2-Br om o-
eth yl)-4-(3,4-d im eth oxyp h en yl)-6,7-d im eth oxyqu in olin e-
3-ca r boxyla te. Ethyl 4-(3,4-dimethoxyphenyl)-2-[(ethoxycar-
bonyl)methyl]-6,7-dimethoxyquinoline-3-carboxylate was pre-
pared in the same manner as described for 3 by reaction of
2-amino-3,4,4′,5-tetramethoxybenzophenone and ethyl ace-
tonedicarboxylate (yield 56%): mp 146-147 °C (EtOH); 1H
NMR (CDCl3) δ 0.97 (3H, t, J ) 7.2 Hz), 1.27 (3H, t, J ) 7.4
Hz), 3.80 (3H, s), 3.87 (3H, s), 3.97 (3H, s), 4.03 (2H, q, J )
7.4 Hz), 4.05 (3H, s), 4.16 (2H, s), 4.20 (2H, q, J ) 7.2 Hz),
6.89-7.02 (4H, m), 7.45 (1H, s).
2. Bon e Resor p tion In h ibitor y Effect. Bone resorption
inhibitory effect was determined by Raisz’s method:16 45Ca
(radioisotope of calcium in 45CaCl2 solution) (50 µCi) was
subcutaneously injected into a Sprague-Dawley rat on the
18th day of pregnancy. On the next day, the abdomen was
opened, and a fetus was aseptically removed. The left and
right humeri (radii and ulnae) were removed under a dissect-
ing microscope, and as much connective tissue and cartilage
as possible were removed. Thus, bone culture samples were
prepared. The bond was incubated in a medium (0.6 mL) of
BCJ b medium (Fitton-J ackson modification; GIBCO Labora-
tories) containing 2 mg/mL bovine serum albumin at 37 °C
for 24 h in an atmosphere of 5% CO2 in air. The bone was
cultured for an additional 2 days in the above medium
containing a final concentration of 10 or 30 µM of a test
compound. This bone was cultivated for 2 days in the resulting
medium. The 45Ca radioactivity in the medium and the 45Ca
radioactivity in the bone were determined. The ratio (%) of
45Ca released from the bone into the medium was calculated
according to the following equation:
A solution of ethyl 4-(3,4-dimethoxyphenyl)-2-[(ethoxycar-
bonyl)methyl]-6,7-dimethoxyquinoline-3-carboxylate (5.8 g,
12.0 mmol) in THF (100 mL) was added dropwise to a stirred
and ice-cooled suspension of LiAlH4 (455 mg, 12.0 mmol) in
THF (50 mL). The mixture was stirred at room temperature
for 30 min, and then brine (2.5 mL) was added. The whole
was stirred vigorously for 30 min, dried over MgSO4, and
concentrated in vacuo. The residue was chromatographed on
SiO2 (150 g) with CHCl3-AcOEt (1:1) to give crystals. Re-
crystallization from AcOEt-hexane gave ethyl 4-(3,4-dimeth-
oxyphenyl)-2-(2-hydroxyethyl)-6,7-dimethoxyquinoline-3-car-
boxylate as colorless prisms (1.8 g, 33%): mp 150-151 °C; 1H
NMR (CDCl3) δ 1.02 (3H, t, J ) 7.2 Hz), 3.18 (2H, t, J ) 5.4
Hz), 3.80 (3H, s), 3.87 (3H, s), 3.97 (3H, s), 4.06 (3H, s), 4.08
(2H, q, J ) 7.2 Hz), 4.17 (2H, t, J ) 5.4 Hz), 4.80 (1H, brs),
6.89-7.02 (4H, m), 7.38 (1H, s). Anal. (C24H27NO7) C,H,N.
PBr3 (1.0 g, 3.9 mmol) was added dropwise to a stirred
solution of ethyl 4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)-
6,7-dimethoxyquinoline-3-carboxylate (1.7 g, 3.9 mmol) in
benzene (50 mL) at room temperature, and the whole was
stirred at 70 °C for 1 h. The reaction mixture was poured into
ice-water, alkalinized with saturated aqueous NaHCO3, and
extracted with CHCl3. The extract was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue
was chromatographed on SiO2 (20 g) with CHCl3-AcOEt (1:
1) to give crystals. Recrystallization from AcOEt-hexane gave
the title compound as colorless prisms (490 mg, 26%): mp
132-133 °C; 1H NMR (CDCl3) δ 1.04 (3H, t, J ) 7.2 Hz), 3.51
(2H, t, J ) 7.2 Hz), 3.79 (3H, s), 3.87 (3H, s), 3.90 (2H, t, J )
7.2 Hz), 3.97 (3H, s), 4.06 (3H, s), 4.10 (2H, q, J ) 7.2 Hz),
6.90-7.01 (4H, m), 7.41 (1H, m). Anal. (C24H26BrNO6) C,H,N.
Meth od G: Gen er a l P r oced u r e for 2-(Ch lor om eth yl)-
qu in a zolin es 4. 2-(Ch lor om eth yl)-4-(3,4-d im eth oxyp h en -
yl)-6,7-d im eth oxyqu in a zolin e. Powdered AlCl3 (6.7 g, 50.2
mmol) was added portionwise to a mixture of 2-amino-3′,4,4′,5-
tetramethoxybenzophenone (8.0 g, 25.2 mmol) and chloroac-
etonitrile (25 mL) at room temperature, and the whole was
stirred at 100 °C for 2 h. The reaction mixture was poured
ratio of 45Ca released from bone into medium (%) )
45Ca released into medium
(
45Ca released into medium) + (45Ca incorporated in bone)
× 100
Bones from the same litter were cultured for 2 days in the
same manner without addition of the compound and used as
a control. The mean of the values for five bones for each group
was calculated. The ratio (%) of this value to the control value
was calculated.
Lactate dehydrogenase (LDH) activity in the medium was
assayed using a commercially available LDH kit (Wako Pure
Chemical Industries, Ltd., Osaka, J apan).
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J M9509408