Synthesis and antitumor evaluation of new thiazolo[5,4-b]quinoline derivatives

Article abstract of DOI:10.1021/jm960556q

A new synthesis of 9-hydroxy- and 9-(alkylamino)thiazolo[5,4- b]quinolines by cyclization of 4-(ethoxycarbonyl)-5-(arylamino)thiazoles and 5-(arylamino)-4-carbamoylthiazoles, respectively, is described. In vitro cytotoxicity of a large number of derivativ

Full text of DOI:10.1021/jm960556q

668
J . Med. Chem. 1997, 40, 668-676
Syn th esis a n d An titu m or Eva lu a tion of New Th ia zolo[5,4-b]qu in olin e
Der iva tives
Carlos Alvarez-Ibarra,* Roc´ıo Ferna´ndez-Granda, Mar´ıa L. Quiroga, Ange´lica Carbonell,
Francisco Ca´rdenas,† and Ernest Giralt†
Departamento de Qu´ımica Orga´nica, Facultad de Quı´mica, Universidad Complutense, Ciudad Universitaria, s/ n. 28040
Madrid, Spain, and Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de Barcelona, c/ Mart´ı i
Franque´s, 1. 08028 Barcelona, Spain
Received J uly 29, 1996X
A new synthesis of 9-hydroxy- and 9-(alkylamino)thiazolo[5,4-b]quinolines by cyclization of
4-(ethoxycarbonyl)-5-(arylamino)thiazoles and 5-(arylamino)-4-carbamoylthiazoles, respectively,
is described. In vitro cytotoxicity of a large number of derivatives of these compounds has
been tested against several cell lines. The highest activities observed are associated with the
presence of a 2-[[(N,N-diethylamino)ethyl]amino] substituent at C-2 and a fluorine atom at
the C-7 position of the tricyclic planar heteroaromatic framework. Three structural features
seem to be essential for antitumor activities: a positive charge density at carbon C-7, a side
chain at position C-2 or C-9 of the thiazoloquinoline skeleton with two basic nitrogens and a
pKa value of 7.5-10 in the most basic center, and a conformational flexibility of this basic side
chain. These structural requirements must be simultaneously satisfied in order to ensure a
significant antitumor activity.
Ch a r t 1
In tr od u ction
Acridine and quinoline derivatives1 have been exten-
sively studied as potential antitumor agents, since they
are capable of binding to DNA.1a Additionally, quina-
crine and related derivatives have also been tested as
antimalarial1a and antineoplastic1d,e,2 agents. The chem-
istry of quinoline derivatives has received particular
attention over the last few years,3 and a large variety
of quinolines has been synthesized and assessed as
antimalarial,4 antiallergic,5 antiinflammatory,6 fungi-
cidal,7 and antiviral8 agents. Among all these deriva-
tives, thiazolo[4,5-g]-, -[5,4-g]-, -[4,5-h]-, -[5,4-h]-, -[4,5-
f]-, and [5,4-f]quinolines9 1 (Chart 1) have shown high
activity as antibacterial agents. On the other hand, the
synthesis of thiazolo[5,4-b]quinoline derivatives 2 has
rarely been reported in the literature.10-12 These
compounds have been described as potential antispas-
modics,13 precursors of symmetrical cyanines,14 antiin-
flammatories,15 and fluorescent probes16 (Chart 1).
The purpose of the present study was the synthesis
of the previously unknown thiazolo[5,4-b]quinoline de-
rivatives 3-10 (Chart 1) and the study of the in vitro
evaluation of these derivatives as potential antitumor
agents. Derivatives 3-10 can be structurally related
to quinolones and acridines by isosteric substitution of
a benzene moiety for a thiazole ring.
Resu lts a n d Discu ssion
Ch em istr y. The synthesis of thiazolo[5,4-b]quinolin-
9-one skeleton 11 can be rationalized by the retrosyn-
thetic pathways outlined in Scheme 1. Thiazolo[5,4-
b]quinoline derivatives were previously obtained by
different methods which can be related to synthetic
pathways I-III (Scheme 1). Tanasescu et al.10,16 have
reported the synthesis of 2-(arylamino)- and 2-(alky-
lamino)thiazolo[5,4-b]quinolines in low yields (50-60%)
by condensation of primary or secondary amines with
2-chloro-3-isothiocyanatoquinolines which were used as
precursors of 12 (Scheme 1, pathway I). Quinolines 13
have been obtained from 2-mercapto-3-aminoquinolines
and transformed into thiazoloquinolones 11 with low
yields (35-60%) (Scheme 1, pathway II). Finally,
pathway III has been previously applied to obtain
2-(arylamino)- or 2-(alkylamino)thiazolo[5,4-b]quino-
lines from 2-aryl- or 2-(alkylamino)-4-thiazolidone13 and
thiazolo[5,4-b]quinolin-2-one from 2,4-thiazolinedione.11
† Universidad de Barcelona.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1997.
S0022-2623(96)00556-0 CCC: $14.00 © 1997 American Chemical Society

Synthesis, Evaluation of Thiazolo[5,4-b]quinolines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 669
Ta ble 1. 1H NMR Chemical Shifts (ppm) of
Thiazolo[5,4-b]quinolines 3-10
Sch em e 1
compda H-5 H-6 H-7 H-8 compda H-5 H-6 H-7 H-8
3a
3b
3c
4a
4b
4c
5a
5b
5c
8.09 7.78 7.67 8.38
6a
6b
6c
7a
7b
7c
8
7.93 7.66 7.62 8.22
7.96 7.59
8.04 7.50
8.12
7.92
7.68 7.37
7.91 7.37
7.83
7.70
8.21 7.91 7.77 8.47
8.00 7.63 7.59 8.25
8.03 7.69
8.21 7.68
8.13
8.05
7.89 7.45
7.95 7.35
8.01
7.81
8.21 7.95 7.79 8.50
7.86 7.59 7.35 7.97
7.74 7.42 8.17
7.83 7.63 7.47 8.21
8.09 7.76
8.23 7.72
8.23
8.09
9
10
a
For numbering of hydrogens, see Chart 1.
cyclization of amides to tricyclic derivatives 8-10 could
be easily afforded with moderate yields by following the
known procedure20 with POCl3/PPA at 130 °C for 15
min.
As far as we know, the synthetic pathway IV using
2-(methylthio)-4-(ethoxycarbonyl)-5-(arylamino)thiaz-
oles 15a -c as precursors of hydroxythiazolo[5,4-b]-
quinolines is reported here for the first time (Scheme
2). Thiazoles 15a -c were obtained in high yields (94-
98%) from ethyl N-[bis(methylthio)methylene]glyci-
nate17,18 and aryl isothiocyanates.19
Free bases 3-10 were transformed to their hydro-
chloride salts30 in order to test their stabilities and to
perform the biological assays. These hydrochlorides
were also used to measure pKa values,31 and their
structural parameters have been previously described.31
2-Methylsulfinyl derivatives 4a -c yielded the 2-chloro-
9-hydroxythiazolo[5,4-b]quinolines 18a -c (Scheme 3).
This competitive reaction pathway may be explained by
intramolecular catalysis of the nucleophilic substitution
of the O-protonated 2-methylsulfinyl derivatives by a
chloride anion in a preformed ion pair.
The synthesis of 9-hydroxythiazolo[5,4-b]quinolines
3a -c was achieved in good yields (63-90%) by reacting
20
aminothiazoles 15a -c in PPA in the presence of POCl3
(Scheme 2). Among all the dehydration reagents de-
scribed in the literature (POCl3, PPA, H2SO4,21 SOCl2,22
(CF3CO)2O23), the POCl3/PPA system offers several
advantages. It is a nonoxidative system which can be
used at high temperature, and it consequently affords
higher yields than other dehydrating reagents. After
several attempts to optimize the reaction conditions, we
found that sulfoxides 4a -c were selectively obtained in
good yields by oxidation of derivatives 3a -c with
MCPBA in dichloromethane24 for 1 h at -15 °C. On
the other hand, sulfones 5a -c were achieved in good
yields by reacting sulfides 3a -c with potassium per-
manganate in an acetic acid-water mixture for 40 min
at 50-70 °C.25
Str u ctu r a l Assign m en t. All thiazolo[5,4-b]quino-
lines 3-10 gave correct elemental analyses, and their
1
structures were confirmed by IR, H NMR (300 MHz)
and 13C NMR (75.5 MHz) spectra. IR spectra of
compounds 4a -c show a strong absorption band at 1060
cm-1 which can be assigned to the stretching vibration
of a sulfoxide group.32 On the other hand, IR spectra
of compounds 5a -c have a strong band at 1170 cm-1
corresponding to the stretching vibration of a sulfone
group.32
The unequivocal assignment of observed signals in the
1H NMR spectra of thiazolo[5,4-b]quinolines 3-10 to
hydrogens H-5/H-8 of the benzene ring was carried out
from the observed chemical shifts (Table 1) and cou-
Earlier studies of the structure-antileukemic rela-
tionships, for congeners of the DNA-intercalating 4′-(9-
acridinylamino)alkanesulfonanilides, demonstrated that
examples bearing a second strongly basic function could
provide exemplary activity in usual screening tests.26
Bearing in mind this possibility, a linking of a [(dialky-
lamino)alkyl]amino function at C-2 and C-9 positions
for studying the effects of these substituents on cyto-
toxicities was considered. Amino substituents at posi-
tion C-2 of the planar tricyclic chromophore of 9-hy-
droxythiazolo[5,4-b]quinolines 6a -c and 7a -c were
introduced in quantitative yields by nucleophilic sub-
stitution of the methanesulfonyl group of derivatives
5a -c with N,N-(diethylamino)ethylenediamine or N-
methylpiperazine, respectively, for 20 min at 140 °C.27
9-(Alkylamino)thiazolo[5,4-b]quinoline derivatives
8-10 were obtained from thiazoles 15a ,b (Scheme 2).
Esters were first hydrolyzed to carboxylic acids 16a ,b
by treatment with KOH/H2O-EtOH which were then
successively reacted with thionyl chloride and the amine
to give amides 17a -c. Cyclization to thiazolo[5,4-b]-
quinoline derivatives was rather difficult: under various
conditions, reaction of amides with POCl3,28 POCl3/
SnCl4/nitrobenzene,29 or POCl3/SnCl4/nitromethane29
led to the formation of a mixture of starting materials
and/or decomposition products. However, we found that
1
plings. The H-19F observed couplings in the spectra
of fluorinated derivatives 3c-7c (see the Experimental
Section) allowed to carry out the assignment proposed
for these compounds (Table 1). Theoretical chemical
shifts of hydrogens H-5, H-6, and H-8 for compounds
3a ,b/7a ,b were calculated from induced chemicals shifts
related in the literature33 for a methyl group and a
fluorine atom. The comparison between observed and
calculated chemical shifts was very satisfactory.34
The assignment proposed in Table 1 for aromatic
hydrogens of compounds 8-10 was supported in the
observed chemical shifts and the splitting of signals.35
The assignment of 13C NMR observed signals (Table 2)
was carried out as follows.
(a ) Assign m en t of Sign a ls to Ca r bon s C-4a , C-5,
C-6, C-7, C-8, a n d C-8a . The signals of methine
carbons should be stronger than signals for carbons C-4a
and C-8a.36 The 13C-19F couplings observed in the
spectra of fluorinated derivatives 3c-7c (see the Ex-
perimental Section) allowed the assignment of all
benzene carbons proposed in Table 2. Theoretical
chemical shifts of these carbons on related unfluorinated
derivatives were calculated from the induced chemical
shifts published38 for a methyl group and a fluorine

670 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Alvarez-Ibarra et al.
Sch em e 2a
a
(i) POCl3/PPA/130 °C/4 h; (ii) MCPBA/CH2Cl2/-15 °C/1 h; (iii) KOH/EtOH-H2O/65 °C/20 min; (iv) KMnO4/AcOH-H2O/55-70 °C/40
min; (v) 140 °C/20 min; (vi) SOCl2/pyr/0 °C/1.5 h; (vii) amine/20 °C/1 h; (viii) POCl3/PPA/130 °C/15 min.
Sch em e 3
of carbons C-9 due to the electronic effects of substitu-
ents bonded to carbon C-2. (iii) The assignment of
signals to carbons C-3a and C-9a could be reasonably
established considering that the carbon C-3a has to be
more deshielded than the carbon C-9a. The first one is
bound to two heteroatoms, and the carbon C-9 is
attached to one heteroatom. Furthermore, chemical
shifts of carbons C-3a and C-9a could be reasonably
estimated as follows. The induced chemical shifts as a
consequence of cyclization of thiazoles 15a -c and
17a -c to thiazolequinolines 3a -c and 8-10, respec-
tively, could be reasonably calculated as 15 ppm for
carbon C-9a and -3 ppm for carbon C-3a. These
induced chemical shifts have been calculated from
chemical shifts described42 for compounds 19 and 20
(Chart 2).
atom in a benzene ring. The comparison between
observed and calculated chemical shifts was very sat-
Thus, the chemical shifts of carbons C-3a and C-9a
could be estimated as the algebraic addition of calcu-
lated induced chemical shifts and the observed averaged
values for carbons C-4 and C-5 on thiazoles 15a -c and
17a -c. These calculations were supported by the
charge densities on carbons C-3a and C-9a calculated
by MNDO43 for tricyclic derivatives 3-10 (Table 3). In
all compounds, except for derivatives 7b,c, the charge
density on carbon C-9a was greater than on carbon C-3a.
isfactory.39 2D-Heteronuclear H-13C (HETCOR) spec-
1
tra strengthened the assignments of methine carbons
proposed in Table 2.
(b) Assign m en t of Sign a ls to Ca r bon s C-2, C-3a ,
C-9, a n d C-9a . These assignments were carried out
as follows. (i) The most deshielded carbons of this group
should be C-2 and C-9. Carbon C-2 is bonded to three
heteroatoms,40 and carbon C-9 is a γ-type atom of a
4-hydroxyquinoline.41 (ii) Chemical shifts of carbons C-2
should vary over a larger range than the chemical shifts
The oxidation of methylsulfenyl derivatives 3a -c to
sulfoxides 4a -c or sulfones 5a -c was very selective,

Synthesis, Evaluation of Thiazolo[5,4-b]quinolines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 671
Ta ble 2. 13C NMR Chemical Shifts (ppm) Observed for Compounds 3-10a
compdb
C-2
C-3a
C-4a
C-5
C-6
C-7
C-8
C-8a
C-9
C-9a
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8
171.8
171.5
172.8
183.3
182.8
184.5
169.3
168.9
171.5
167.0
167.0
167.3
166.4
166.5
171.4
163.6
162.4
164.0
145.9
144.6
142.9c
147.0
146.0
144.5
148.5
147.4
145.8d
145.4
144.2f
144.7
144.4
144.9
143.5
146.6
146.0
147.1i
130.6
131.3
129.8
135.9
134.9
135.0
138.5
138.2
131.3
126.6
126.5
124.7
125.4g
125.3
124.1
142.4
142.5
137.7
128.2
128.0
130.9
128.7
128.3
131.6
128.8
128.4
131.7
128.5e
128.2
131.3
127.9
127.6
130.3
128.3h
130.2
128.2j
129.4
131.7
119.9
131.1
133.6
122.0
131.8
134.4
122.8
128.8e
130.9
118.4
127.4
129.8
117.4
128.6h
125.1
128.5j
126.7
136.9
160.7
127.4
137.7
160.9
127.8
137.4
161.0
127.7
138.0
162.0
126.3
136.3
160.5
122.9
127.9
125.2
124.4
123.0
108.0
124.6
123.4
108.1
124.9
123.3
108.2
124.6
123.4
108.1
123.6
122.5
107.4
121.8
121.4
124.2
124.6
124.5
125.7
124.6
124.6
125.8
125.0
124.9
126.1
126.0
125.5
127.6
125.3g
124.7
126.5
117.3
124.4
123.5
160.3
159.2
159.6
159.0
157.9
158.5
158.8
157.7
164.7
160.2
164.2
159.6
158.6
157.9
157.8
158.5
157.6
162.9
141.8
141.8
142.2c
144.9
142.3
142.9
140.9
140.9
144.9d
144.3
144.0f
142.2
143.0
143.0
141.2
145.0
145.0
147.2i
9
10
a
b
For signals of aromatic tricyclic backbone substituents, see the Experimental Section. For numbering of carbons, see Chart 1.
c Interchangeable assignments.
Ch a r t 2
F igu r e 1. 13C NMR induced chemical shifts on thiazole
carbons and the methyl group by oxidation of the SMe group
to SOMe and SO2Me.
Ta ble 4. 13C NMR Induced Chemical Shiftsa on Carbons C-2,
C-3a, C-4a, and C-9 and Methyl Groups for Derivatives 4a -c
and 5a -c
compd
n
∆SOnCH3
∆C-2
∆C-3a
∆C-4a
∆C-9
4a
4b
4c
5a
5b
5c
1
1
1
2
2
2
27.5
27.6
27.6
26.2
26.2
26.1
11.5
11.3
11.7
-2.5
-2.6
-1.3
1.1
1.4
1.6
2.6
2.8
2.9
5.3
3.6
5.2
7.9
6.9
1.5
-1.3
-1.3
-1.1
-1.5
-1.5
5.1
a
Calculated as the difference between chemical shifts observed
for the oxidized derivative and the unoxidized precursor.
Ta ble 3. Charge Densities Calculated by MNDO on Carbons
C-3a and C-9a of Compounds 3-10
compd
QC-3a
QC-9a
compd
QC-3a
QC-9a
3a
3b
3c
4a
4b
4c
5a
5b
5c
-0.089
-0.089
-0.093
-0.096
-0.100
-0.074
-0.095
-0.081
-0.090
-0.186
-0.224
-0.178
-0.157
-0.154
-0.215
-0.154
-0.229
-0.214
6a
6b
6c
7a
7b
7c
8
-0.096
-0.096
-0.098
-0.181
-0.183
-0.186
-0.102
-0.093
-0.111
-0.176
-0.179
-0.141
-0.192
-0.172
-0.166
-0.128
-0.152
-0.117
F igu r e 2. 13C NMR induced chemical shifts by N-oxidation.
13C NMR chemical shifts induced by an N-oxidation
of a pyridine nitrogen can be calculated from data
reported for pyridine,42 quinoline,44 and their N-oxides
(Figure 2). The N-oxidation causes a clear shielding of
R- and γ-carbons (≈ -10 ppm). However, the observed
chemical shifts for these carbons in compounds 4 and 5
do not support the N-oxidation hypothesis (Table 4):
carbons C-3a and C-4a of derivatives 4 and 5 and the
carbon C-9 of compound 5c show a clear deshielding of
these signals, whereas the observed shieldings for
carbon C-9 on derivatives 4a -c and 5a ,b were much
lower than -10 ppm.
9
10
and the N-oxidation was not observed as demonstrated
by the 13C NMR spectroscopic data. Induced chemical
shifts on carbons C-2 and C-3a and the methyl group
by the oxidation of the methylsulfenyl group to SOMe
and SO2Me can be estimated from the 13C NMR data
reported27c for thiazoles 21 and 22 (Figure 1). The
induced chemical shifts of carbons C-2 and C-3a and
the methyl group for derivatives 4a -c and 5a -c have
been gathered in Table 4. Calculated values for these
parameters are practically identical with estimated
values from literature data27c (Figure 1).
Cytotoxicity Resu lts a n d Discu ssion . The results
of the evaluation of thiazolo[5,4-b]quinolines 3a -c,
5-10, and 18a -c against the proliferation of mouse
lymphoid neoplasm (P-388), human lung carcinoma (A-

672 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Alvarez-Ibarra et al.
Ta ble 5. Physicochemical Properties and Biological Data for
Thiazolo[5,4-b]quinolines 3, 5-10, and 18a -c
Ch a r t 3
IC50 (µM) (in vitro)d
compda QC-7
pKa
P-388 ((SE) A-549 ((SE) HT-29 ((SE)
b
c
3a
3b
3c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8
-0.076 5.9e >70.2
-0.116 4.6e >66.9
0.131 5.7e >66.1
>70.2
>66.9
>66.1
32.4 (0.9)
>60.4
6.0 (0.8)
>70.2
>66.9
>66.1
32.4 (0.9)
>60.4
6.0 (0.8)
-0.056 5.2e
32.4 (0.9)
-0.113 4.0e >60.4
0.134 5.5e
-0.076 9.3f
-0.115 8.4f
0.132 8.3f
6.0 (0.8)
5.76 (0.07)
3.3 (0.3)
1.65 (0.05)
18.8 (0.3)
16.9 (0.6)
7.22 (0.02)
5.6 (0.2)
2.9 (0.3)
7.22 (0.02)
3.3 (0.2)
5.0 (0.5)
-0.143 8.6g
-0.080 10.0g
18.8 (0.3)
29.6 (1.0)
>56.4
6.0 (0.7)
5.4 (0.5)
12.1 (0.9)
11.6 (0.9)
34.6 (0.7)
7.4 (1.1)
18.8 (0.3)
17.0 (0.3)
>56.4
6.0 (0.7)
5.4 (0.5)
12.1 (0.9)
11.6 (0.9)
34.6 (0.7)
7.4 (1.1)
0.079 8.0g >56.4
-0.065 7.5h
-0.110 7.9h
-0.069 6.5h
-0.079 5.9e
-0.114 5.0e
0.134 4.9e
6.0 (0.7)
9
5.4 (0.5)
12.1 (0.9)
5.3 (0.4)
34.6 (0.7)
7.4 (1.1)
10
18a
18b
18c
a
b
Tested as hydrochloride salts. Charge density at carbon C-7
calculated by MNDO.43 c pKa values were determined by dif-
ferential pulse polarography as detailed in ref 31. SE: standard
d
error. Analytical data were fitted to a sigmoid function with the
Fig. P software46 with excellent regression correlation coefficients
(0.994-0.999). e Protonation of the quinoline nitrogen. f Protona-
g
tion of the nitrogen of the N,N-diethylamino group. Protonation
h
of nitrogen N-4 of the 4-methyl-1-piperazinyl group. Protonation
of the nitrogen of the N,N-diethylamino group (compounds 8 and
9) or the N,N-dimethylamino group (compound 10).
simultaneously satisfied in order to ensure a significant
antitumor activity.
549), and human colon tumor (HT-29) cell lines in vitro
are shown in Table 5.45
The charge density at the C-7 carbon must be positive.
Substitution with a fluorine atom resulted in a signifi-
cant decrease of charge density on this carbon, as seen
from a comparison of fluorinated derivatives 3c, 5c, 6c,
7c, and 18c with their methyl-substituted analogs 3b,
5b, 6b, 7b, and 18b or unsubstituted congeners 3a , 5a ,
6a , 7a , and 18a . These results suggest that an electron-
withdrawing group at the C-7 position seems to be
significant for the antitumor activity.
Substitution of a flexible [(N,N-diethylamino)ethyl]-
amino side chain at the C-2 position by a 1-(4-meth-
ylpiperazinyl) group was shown to be critical for anti-
tumor activity (compare IC50 values for compounds
6a -c to IC50 data for compounds 7a -c, respectively).
The pKa of the side chain had a significant influence on
the cytotoxicity of thiazolo[5,4-b]quinoline derivatives:
a pKa value less than 7.5, which is associated with the
presence of a side chain with two basic amine nitrogens,
could be related to a significant decrease of activity.
Some interesting comparisons of cytotoxic activities
described in this paper for thiazolo[5,4-b]quinolines with
data previously published for acridine and quinoline
derivatives can be made.48 Cytotoxic activities of a new
class of acridine alkaloids which possesses a thiazolo-
[5,4-b]acridine nucleus (23-28) (Chart 3) have been
recently reported.49,50 It was found that compounds 23-
26 and 28 displayed an antitumor activity comparable
to that of thiazolo[5,4-b]quinolines 5c, 6a -c, 7a ,b,
8-10, and 18a ,c, whereas the compound 27 has an
activity slightly higher than derivative 6c.
Some information on structure-activity relationships
can be identified as follows. (a) It is clear from these
data that the compound 6c has the highest levels of
cytotoxicity against P-388 and A-549 cell lines. (b) Both
the fluorine atom at the C-7 position and the [(N,N-
diethylamino)ethyl]amino group at the C-2 carbon seem
to be important for the induction of significant antitu-
mor activities. Comparing the thiazolo[5,4-b]quinolines
with an identical group at C-2, the change of the fluorine
atom at C-7 to a methyl group or hydrogen atom was
shown to be very important for antitumor activity
against all three tested tumor types (compare IC50
values of fluorinated derivatives 3c, 5c, 6c, and 18c
with IC50 data from methyl-substituted compounds 3b,
5b, 6b, and 18b and unsubstituted derivatives 3a , 5a ,
6a , and 18a .47 Compounds 3a -c, 5a -c, and 18a -c
lacking one NCH2CH2N side chain at C-2 were not
effective against all three tumor types (3a -c) or were
less active than derivatives 6a -c. (c) The difference of
the substitution at C-2 between the [(N,N-diethylami-
no)ethyl]amino and 1-(4-methylpiperazinyl) groups was
shown to be critical for antitumor activity (compare IC50
values of 6a -c to IC50 data of 7a -c, respectively). (d)
The change of the [(N,N-dialkylamino)alkyl]amino group
at C-2 to the C-9 position resulted in a slight decrease
of IC50 values for compounds 8 and 9 and in a large
decrease of activities for compound 10, as seen from a
comparison in IC50 data of 6a to 8 or 10 and also 6b to
9.
In the light of the activities displayed in Table 5, three
structural features seem essential for antitumor activi-
ties in vitro: the charge density induced by the sub-
stituent at C-7 position, the pKa value, and the confor-
mational flexibility on the basic side chain at the C-2
position. These three structural requirements must be
Wetland et al. have recently reported some antitumor
activities of 3-benzylquinolones 2951 and pyrazoloquino-
lines 3052 against the proliferation of mice lymphoid
neoplasm P-388 (in vitro) (Chart 3). Thirteen quinolo-
nes 29 proved to be as equally active as some of our
thiazoloquinolines, and six derivatives were shown to

Synthesis, Evaluation of Thiazolo[5,4-b]quinolines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 673
(CHCl3) ν 3660, 3390, 1590, 1550, 1500 cm-1; 1H NMR (CDCl3)
be slightly more active (IC50: 0.3-0.9 µM) than deriva-
tive 6c. Thirteen quinolines 30 (Chart 3) showed an
antitumor activity comparable to that of thiazoloquino-
line 6c, seven derivatives were slightly better than
compound 6c (IC50: 0.2-0.4 µM), and only two deriva-
tives 29 ((R)-4-(1-methylpiperidinyl)-, 4-[(1-N,N-di-
methylamino)cyclohexyl]) showed to be more active
(IC50: 0.07-0.10 µM) than compound 6c.
4
δ 2.61 (3H, s), 2.88 (3H, s), 7.59 (1H, dd, 3J ) 8.7 Hz, J ) 2.1
3
5
4
Hz), 7.96 (1H, dd, J ) 8.7 Hz, J ) 0.6 Hz), 8.12 (1H, dd, J
) 2.1 Hz, J ) 0.6 Hz); 13C NMR (CDCl3) δ 15.2, 21.7, 123.0,
124.5, 128.0, 131.3, 131.7, 136.9, 141.8, 144.6, 159.2, 171.5.
Anal. (C12H10N2S2O) C, H, N.
5
7-F lu or o-9-h yd r oxy-2-(m eth ylth io)th ia zolo[5,4-b]qu in -
olin e, 3c: white solid (74%); mp 182-4 °C (ethyl acetate); IR
(CHCl3) ν 3660, 3390, 1590, 1550, 1500 cm-1; 1H NMR (CDCl3)
3
4
δ 2.88 (3H, s), 7.50 (1H, ddd, J ) 9.3, 7.8 Hz, J ) 2.9 Hz),
3
4
3
7.92 (1H, dd, J ) 9.8 Hz, J ) 2.9 Hz), 8.04 (1H, dd, J ) 9.3
Con clu sion s
Hz, 4J ) 5.1 Hz); 13C NMR (CDCl3) δ 15.3, 108.0 (d, J C,F
)
2
Two new series of thiazolo[5,4-b]quinoline derivatives,
namely, 9-hydroxy- and 9-[[(N,N-dialkylamino)propyl]-
amino]thiazolo[5,4-b]quinolines, were synthesized in
high yields. The preliminary antitumor studies of these
thiazolo[5,4-b]quinoline derivatives showed that 7-fluoro-
2-[[(N,N-diethylamino)ethyl]amino]thiazolo[5,4-b]quino-
lines exhibited significant cytotoxicity against mouse
leukemic P-388, human lung carcinoma A-549, and
human colon tumor HT-29 cell growth in vitro. Three
structural features seem to be essential for antitumor
activities: a positive charge density, induced by the
substituent, at carbon C-7, a side chain at position C-2
or C-9 of the tricyclic system with two basic nitrogens
and a pKa value of 7.5-10, and conformational flexibility
of this basic side chain. All these structural require-
ments must be simultaneously satisfied to ensure
significant antitumor activity.
2
3
25.2 Hz), 119.9 (d, J C,F ) 26.2 Hz), 125.7 (d, J C,F ) 10.0 Hz),
129.8 (d, 4J C,F ) 6.0 Hz), 130.9 (d, 3J C,F ) 9.0 Hz), 142.2, 142.9,
1
159.6, 160.7 (d, J C,F ) 248.8 Hz), 172.8. Anal. (C11H7N2S2-
OF) C, H, N.
Oxid a tion of 3a -c w ith m -Ch lor op er ben zoic Acid .
Gen er a l P r oced u r e. To a solution of 3a -c (0.8 mmol) in
CH2Cl2 (5 mL) at -15 °C was added m-chloroperbenzoic acid
(0.8 mmol), and the mixture was stirred for 1 h at -15 °C.
The reaction mixture was then allowed to reach room tem-
perature, washed successively with a 5% aqueous solution of
Na2S2O3 (3 × 5 mL), a 50% aqueous solution of NaHCO3 (3 ×
5 mL), and brine (3 × 10 mL), and dried over MgSO4. After
concentration of the solution, the pale yellow crude solid was
recrystallized from methanol.
9-H yd r oxy-2-(m e t h ylsu lfin yl)t h ia zolo[5,4-b]q u in o-
lin e, 4a : white solid (85%); mp 151-3 °C (CH3OH); IR (CHCl3)
1
ν 3680, 3400, 1590, 1550, 1490, 1060 cm-1; H NMR (CDCl3)
3
4
δ 3.20 (3H, s), 7.77 (1H, ddd, J ) 8.7, 6.9 Hz, J ) 1.2 Hz),
7.91 (1H, ddd, 3J ) 8.4, 6.9 Hz, 4J ) 1.5 Hz), 8.21 (1H, ddd, 3J
4
5
3
) 8.4 Hz, J ) 1.2 Hz, J ) 0.6 Hz), 8.47 (1H, ddd, J ) 8.7
Hz, 4J ) 1.5 Hz, 5J ) 0.6 Hz).; 13C NMR (CDCl3) δ 42.8, 124.6,
124.6, 127.4, 128.7, 131.1, 135.9, 144.9, 147.0, 159.0, 183.3.
Anal. (C11H8N2S2O2) C, H, N.
Exp er im en ta l Section
All starting materials were commercially available research-
grade chemicals and used without further purification. 2-(Meth-
ylthio)-4-(ethoxycarbonyl)-5-(arylamino)thiazoles 15a -c were
prepared according to the previously described procedure.19
Analytical TLC was performed using silica gel 60 F254 with
UV light detection. Flash column chromatography was carried
out on silica gel 60. IR spectra were recorded as KBr solid
pellets or as CHCl3 solutions in 0.1 mm NaCl cells with
compensation. Melting points are uncorrected. 1H and 13C
NMR spectra were recorded at 300 and 75.5 MHz, respectively,
in CDCl3 or CD3OD solutions with TMS as internal reference.
The Eagle’s minimum essential medium with Earle’s bal-
anced salts, with nonessential amino acids with 2.0 mM
L-glutamine, and without sodium bicarbonate (EMEM) was
purchased from J RH Biosciences. Fetal calf serum (FCS) and
the trypsin were obtained from Seromed.
Cycliza t ion of 5-(Ar yla m in o)-4-(et h oxyca r b on yl)-2-
(m et h ylt h io)t h ia zoles 15a -c t o 9-H yd r oxy-2-(m et h yl-
th io)th ia zolo[5,4-b]qu in olin es 3a-c. Gen er a l P r oced u r e.
To 15a -c (1 mmol) at 20 °C were successively added POCl3
(470 mg) and PPA (71 mg). The mixture was vigorously stirred
for 4 h at 130-5 °C. The mixture was then cooled to room
temperature, 1 mL of ethanol was added, and the reaction
mixture was concentrated at reduced pressure. The reaction
was hydrolyzed with H2O (10 mL) and neutralized with a 20%
aqueous solution of NaHCO3. The solution was then extracted
with CHCl3 (3 × 5 mL), and the combined organic layers were
washed with brine (3 × 5 mL) and dried over Na2SO4. After
concentration of the solution, the pale yellow crude product
was purified by flash chromatography (hexane/ethyl acetate:
80/20).
9-Hyd r oxy-7-m eth yl-2-(m eth ylsu lfin yl)th ia zolo[5,4-b]-
qu in olin e, 4b: white solid (95%); mp 172-3 °C (CH3OH); IR
1
(CHCl3) ν 3680, 3400, 1590, 1550, 1500, 1060 cm-1; H NMR
3
(CDCl3) δ 2.64 (3H, s), 3.19 (3H, s), 7.69 (1H, dd, J ) 8.7 Hz,
3
4
4J ) 1.8 Hz), 8.03 (1H, d, J ) 8.7 Hz), 8.13 (1H, d, J ) 1.8
Hz); 13C NMR (CDCl3) δ 21.8, 42.8, 123.4, 124.6, 128.3, 133.6,
134.9, 137.7, 142.3, 146.0, 157.9, 182.8. Anal. (C12H10N2S2O2)
C, H, N.
7-F lu or o-9-h yd r oxy-2-(m eth ylsu lfin yl)th ia zolo[5,4-b]-
qu in olin e, 4c: white solid (88%); mp 126-7 °C (CH3OH); IR
1
(CHCl3) ν 3680, 3400, 1590, 1550, 1490, 1060 cm-1; H NMR
(CDCl3) δ 3.20 (3H, s), 7.68 (1H, ddd, 3J ) 9.4, 7.7 Hz, 4J )
3
4
2.8 Hz), 8.05 (1H, dd, J ) 9.4 Hz, J ) 2.8 Hz), 8.21 (1H, dd,
3J ) 9.5 Hz, J ) 5.1 Hz); 13C NMR (CDCl3) δ 42.9, 108.1 (d,
4
2J C,F ) 25.2 Hz), 122.0 (d, J C,F ) 26.3 Hz), 125.8 (d, J C,F
)
2
3
3
4
9.9 Hz), 131.6 (d, J C,F ) 9.9 Hz), 135.0 (d, J C,F ) 6.6 Hz),
1
142.9, 144.5, 158.5, 160.9 (d, J C,F ) 250.8 Hz), 184.5. Anal.
(C11H7N2S2O2F) C, H, N.
Oxid a tion of 3a -c w ith KMn O4. Gen er a l P r oced u r e.
To a solution of 3a -c (0.8 mmol) in glacial AcOH (10 mL) at
55-70 °C was slowly added (40 min) 6 mL of an aqueous
solution of KMnO4 (1.6 mmol). After addition, the reaction
mixture was cooled to room temperature, and 0.13 mL of a
saturated aqueous solution of sodium bisulfite and 4.5 mL of
an 80% aqueous solution of NH4OH were added. The mixture
was then extracted with CHCl3 (3 × 25 mL), and the combined
organic layers were successively washed with a 5% aqueous
solution of NaHCO3 (3 × 25 mL) and brine (3 × 25 mL) and
dried over Na2SO4. After concentration of the solution at
reduced pressure, the pale yellow crude solid was purified by
recrystallization on ethyl acetate.
9-Hyd r oxy-2-(m eth ylth io)th ia zolo[5,4-b]qu in olin e, 3a :
white solid (90%); mp 162-4 °C (ethyl acetate); IR (CHCl3) ν
3660, 3380, 1590, 1550 cm-1; 1H NMR (CDCl3) δ 2.89 (3H, s),
7.67 (1H, ddd, 3J ) 8.4, 6.9 Hz, 4J ) 1.2 Hz), 7.78 (1H, ddd, 3J
9-H yd r oxy-2-(m e t h ylsu lfon yl)t h ia zolo[5,4-b]q u in o-
lin e, 5a : white solid (84%); mp 205-7 °C (ethyl acetate); IR
4
3
4
1
(CHCl3) ν 3680, 3400, 1590, 1550, 1500, 1170 cm-1; H NMR
) 8.4, 6.9 Hz, J ) 1.5 Hz), 8.09 (1H, ddd, J ) 8.4 Hz, J )
5
3
4
(CDCl3) δ 3.53 (3H, s), 7.79 (1H, ddd, 3J ) 8.7, 6.9 Hz, 4J )
1.2 Hz), 7.95 (1H, ddd, 3J ) 8.4, 6.9 Hz, 4J ) 1.5 Hz), 8.21
(1H, ddd, 3J ) 8.4 Hz, 4J ) 1.2 Hz, 5J ) 0.6 Hz), 8.50 (1H,
1.2 Hz, J ) 0.6 Hz), 8.38 (1H, ddd, J ) 8.4 Hz, J ) 1.5 Hz,
5J ) 0.6 Hz); 13C NMR (CDCl3) δ 15.3, 124.4, 124.6, 126.7,
128.2, 129.4, 130.6, 141.8, 145.9, 160.3, 171.8. Anal.
(C11H8N2S2O) C, H, N.
3
4
5
ddd, J ) 8.7 Hz, J ) 1.5 Hz, J ) 0.6 Hz) 13C NMR (CDCl3)
δ 41.5, 124.9, 125.0, 127.8, 128.8, 131.8, 138.5, 140.9, 148.5,
158.8, 169.3. Anal. (C11H8N2S2O3) C, H, N.
9-Hydr oxy-7-m eth yl-2-(m eth ylth io)th iazolo[5,4-b]qu in -
olin e, 3b: white solid (63%); mp 172-3 °C (ethyl acetate); IR

674 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Alvarez-Ibarra et al.
9-Hyd r oxy-7-m eth yl-2-(m eth ylsu lfon yl)th ia zolo[5,4-b]-
qu in olin e, 5b: white solid (90%); mp 204-5 °C (ethyl acetate);
IR (CHCl3) ν 3680, 3400, 1590, 1550, 1500, 1170 cm-1; 1H NMR
(CHCl3) ν 3660, 3400, 1600, 1550, 1450 cm-1; 1H NMR (CDCl3)
δ 2.38 (3H, s), 2.58 (3H, s), 2.58 (4H, t, 3J ) 5.2 Hz), 3.81 (4H,
3
3
4
t, J ) 5.2 Hz), 7.45 (1H, dd, J ) 8.7 Hz, J ) 1.8 Hz), 7.89
(1H, d, 3J ) 8.7 Hz), 8.01 (1H, d, 4J ) 1.8 Hz); 13C NMR (CDCl3)
δ 21.7, 46.0, 47.8, 54.1, 122.5, 124.7, 125.3, 127.6, 129.8, 136.3,
143.0, 144.9, 157.9, 166.5. Anal. (C16H18N4SO) C, H, N.
7-Flu or o-9-h ydr oxy-2-(4-m eth ylpiper azin -1-yl)th iazolo-
[5,4-b]qu in olin e, 7c: white solid (94%); mp 187-8 °C; IR
(CHCl3) ν 3660, 3400, 1605, 1545, 1450 cm-1; 1H NMR (CDCl3)
3
(CDCl3) δ 2.67 (3H, s), 3.52 (3H, s), 7.76 (1H, dd, J ) 8.7 Hz,
4J ) 1.8 Hz), 8.09 (1H, d, 3J ) 8.7 Hz), 8.23 (1H, br s); 13C
NMR (CDCl3) δ 21.9, 41.5, 123.3, 124.9, 128.4, 134.4, 137.4,
138.2, 140.9, 147.4, 157.7, 168.9. Anal. (C12H10N2S2O3) C, H,
N.
7-F lu or o-9-h yd r oxy-2-(m eth ylsu lfon yl)th ia zolo[5,4-b]-
qu in olin e, 5c: white solid (82%); mp 230-1 °C (ethyl acetate);
3
3
δ 2.38 (3H, s), 2.58 (4H, t, J ) 5.6 Hz), 3.80 (4H, t, J ) 5.6
IR (CHCl3) ν 3400, 1590, 1550, 1500, 1170 cm-1
;
1H NMR
Hz), 7.35 (1H, ddd, J ) 9.1, 7.9 Hz, J ) 2.7 Hz), 7.81 (1H,
3 4 3 4
3
4
(CDCl3) δ 3.53 (3H, s), 7.72 (1H, ddd, 3J ) 9.5, 7.6 Hz, 4J )
dd, J )10.2 Hz, J ) 2.7 Hz), 7.95 (1H, dd, J ) 9.1 Hz, J )
2
3
4
2.8 Hz), 8.09 (1H, dd, J ) 9.4 Hz, J ) 2.8 Hz), 8.23 (1H, dd,
5.4 Hz); 13C NMR (CDCl3) δ 45.9, 47.9, 54.1, 107.4 (d, J C,F
)
2 4
3J ) 9.5 Hz, J ) 5.4 Hz); 13C NMR (CDCl3) δ 41.4, 108.2 (d,
25.2 Hz), 117.4 (d, J C,F ) 25.2 Hz), 124.1 (d, J C,F ) 6.0 Hz),
3 3
4
2J C,F ) 25.2 Hz), 122.8 (d, J C,F ) 27.1 Hz), 126.1 (d, J C,F
)
126.5 (d, J C,F ) 10.1 Hz), 130.3 (d, J C,F ) 10.1 Hz), 141.2,
143.5, 157.8, 160.5 (d, 1J C,F ) 246.8 Hz), 171.4. Anal. (C15H15N4-
SOF) C, H, N.
2
3
4
3
7.0 Hz), 131.3 (d, J C,F ) 7.0 Hz), 131.7 (d, J C,F ) 10.1 Hz),
1
144.9, 145.8, 161.0 (d, J C,F ) 252.8 Hz), 164.7, 171.5. Anal.
(C11H7N2S2O3F) C, H, N.
Syn t h esis of 5-(Ar yla m in o)-4-[[3-(N,N-d iet h yl(or d i-
m et h yl)a m in o)p r op yl]ca r b a m oyl]-2-(m et h ylt h io)t h ia -
zoles. Gen er a l P r oced u r e. The carboxylic acids used as
precursors of the amides 17a -c were obtained with good yields
(75%) by saponification of esters 15a ,b following a standard
procedure.53 To a suspension of the carboxylic acid (11.4 mmol)
in dry benzene (35 mL) and dry pyridine (11.3 mmol) at 0 °C
was slowly added thionyl chloride (33.9 mmol). The mixture
was then vigorously stirred at 0 °C for 1.5 h, and the benzene
and excess thionyl chloride were eliminated at reduced pres-
sure. After consecutive addition of dry benzene (25 mL) and
N,N,N′-trimethyl-1,3-propylidenediamine (22.6 mmol), the
reaction mixture was stirred at room temperature for 1 h, and
H2O (50 mL) and CHCl3 (50 mL) were added. The aqueous
layer was extracted with CHCl3 (3 × 30 mL), and the combined
organic layers were successively washed with a 5% aqueous
solution of NaHCO3 (3 × 25 mL), a saturated solution of NH4-
Cl (3 × 25 mL) and brine (3 × 25 mL), and dried over Na2SO4.
The organic phase was evaporated to dryness under reduced
pressure, and the pale yellow oil was purified by flash
chromatography (CH2Cl2/CH3OH: 90/10).
Syn th esis of 2-(Alk yla m in o)-9-h yd r oxyth ia zolo[5,4-b]-
qu in olin es 6a -c a n d 7a -c. Gen er a l P r oced u r e. A solu-
tion of 5a -c (1 mmol) in N,N-diethylethylenediamine (3 mmol)
or N-methylpiperazine (3 mmol) was stirred for 20 min at 140
°C. The reaction mixture was then cooled to room tempera-
ture. Chloroform (20 mL) was then added, and the resulting
solution was successively extracted with a 1 N NaOH solution
(3 × 10 mL), a saturated aqueous solution of NH4Cl (3 × 10
mL), and brine (3 × 10 mL) and dried over Na2SO4. After
concentration of the solution under reduced pressure, the pale
yellow crude product was purified by preparative TLC (twice)
(6a -c) (methanol) or by flash chromatography (ethyl
acetate/methanol: 90/10) and preparative TLC (ethyl
acetate/methanol: 95/5) (7a -c).
2-[[2-(N,N-Dieth yla m in o)eth yl]a m in o]-9-h yd r oxyth ia -
zolo[5,4-b]qu in olin e, 6a : white solid (91%); mp 128-30 °C;
IR (CHCl3) ν 3360, 3320, 1605, 1550, 1460 cm-1 1H NMR
;
(CD3OD) δ 1.23 (6H, t, 3J ) 7.2 Hz), 2.95 (4H, q, 3J ) 7.2 Hz),
3
3
3.10 (2H, t, J ) 6.6 Hz), 3.81 (2H, t, J ) 6.6 Hz), 7.62 (1H,
ddd, 3J ) 8.4, 6.9 Hz, 4J ) 1.5 Hz), 7.66 (1H, ddd, 3J ) 8.4, 6.9
Hz, J ) 1.8 Hz), 7.93 (1H, ddd, J ) 8.4 Hz, J ) 1.5 Hz, J
) 0.6 Hz), 8.22 (1H, ddd, J ) 8.7 Hz, J ) 1.8 Hz, J ) 0.6
Hz); 13C NMR (CD3OD) δ 11.6, 42.3, 48.5, 52.2, 124.6, 126.0,
126.6, 127.7, 128.5, 128.8, 144.3, 145.4, 160.2, 167.0. Anal.
(C16H20N4SO) C, H, N.
4
3
4
5
4-[[3-(N,N-Dieth yla m in o)p r op yl]ca r ba m oyl]-2-(m eth -
ylth io)-5-(p h en yla m in o)th ia zole, 17a : colorless oil (74%);
IR (KBr) ν 3680, 3400, 1670, 1610, 1590, 1550 cm-1; 1H NMR
3
4
5
3
3
(CDCl3) δ 1.08 (6H, t, J ) 7.0 Hz), 1.79 (2H, quint, J ) 6.6
3
3
Hz), 2.63 (3H, s), 2.77 (2H, t, J ) 7.2 Hz), 2.78 (4H, q, J )
2-[[2-(N,N-Diet h yla m in o)et h yl]a m in o]-9-h yd r oxy-7-
m eth ylth ia zolo[5,4-b]qu in olin e, 6b: white solid (95%); mp
7.0 Hz), 3.49 (2H, q, 3J ) 6.3 Hz), 7.02 (2H, t, 3J ) 7.0 Hz),
3
3
7.16 (2H, d, J ) 7.0 Hz), 7.33 (2H, t, J ) 7.0 Hz), 7.91 (1H,
3
107-8 °C; IR (CHCl3) ν 3360, 3320, 1605, 1550, 1460 cm-1
;
br t, J ) 6.3 Hz); 13C NMR (CDCl3) δ 11.3, 17.3, 26.1, 38.2,
1H NMR (CD3OD) δ 1.13 (6H, t, 3J ) 7.2 Hz), 2.50 (3H, s),
46.7, 51.3, 116.8, 122.4, 125.4, 129.4, 140.9, 145.9, 150.2, 164.4.
4-[[3-(N,N-Dieth yla m in o)p r op yl]ca r ba m oyl]-2-(m eth -
ylth io)-5-(p-tolyla m in o)th ia zole, 17b: colorless oil (70%); IR
3
3
2.70 (4H, q, J ) 7.2 Hz), 2.85 (2H, t, J ) 6.9 Hz), 3.66 (2H,
3
3
4
t, J ) 7.8 Hz), 7.37 (1H, dd, J ) 8.7 Hz, J ) 1.5 Hz), 7.68
(1H, d, 3J ) 8.7 Hz), 7.83 (1H, br s); 13C NMR (CD3OD) δ 11.7,
21.9, 42.4, 48.3, 52.2, 123.4, 125.5, 126.5, 128.2, 130.9, 138.0,
144.0, 144.2, 164.2, 167.0. Anal. (C17H22N4SO) C, H, N.
2-[[2-(N,N-Diet h yla m in o)et h yl]a m in o]-7-flu or o-9-h y-
d r oxyth ia zolo[5,4-b]qu in olin e, 6c: white solid (97%); mp
(KBr) ν 3680, 3400, 1670, 1610, 1590, 1550 cm-1
;
1H NMR
3
3
(CDCl3) δ 1.23 (6H, t, J ) 7.0 Hz), 2.04 (2H, quint, J ) 7.0
3
Hz), 2.25 (3H, s), 2.67 (3H, s), 2.77 (4H, q, J ) 7.0 Hz), 2.95
3
3
3
(2H, t, J ) 7.2 Hz), 3.43 (2H, q, J ) 6.3 Hz), 7.00 (2H, t, J
3
3
) 7.0 Hz), 7.15 (2H, d, J ) 7.0 Hz), 7.75 (1H, br t, J ) 6.3
Hz); 13C NMR (CDCl3) δ 11.4, 17.3, 20.5, 26.4, 38.3, 48.8, 51.3,
116.6, 124.9, 127.3, 129.9, 138.7, 145.3, 151.0, 164.4.
120-5 °C; IR (CHCl3) ν 3360, 3320, 1630, 1550, 1460 cm-1
;
1H NMR (CD3OD) δ 1.11 (6H, t, J ) 7.2 Hz), 2.74 (4H, q, J
3
3
3
3
) 7.2 Hz), 2.88 (2H, t, J ) 7.0 Hz), 3.69 (2H, t, J ) 6.9 Hz),
4-[N-Met h yl[3-(N′,N′-d im et h yla m in o)p r op yl]ca r b a m -
oyl]-2-(m eth ylth io)-5-(p h en yla m in o)th ia zole, 17c: color-
less oil (89%); IR (KBr) ν 1635, 1600, 1550 cm-1; two rotamers
A (52%) and B (48%) observed by NMR, 1H NMR (CDCl3)
rotamer A δ 1.91 (2H, br q, 3J ) 7.2 Hz), 2.28 (6H, s), 2.38
3
4
3
7.37 (1H, ddd, J ) 9.3, 8.7 Hz, J ) 2.8 Hz), 7.70 (1H, dd, J
4
3
4
) 10.2 Hz, J ) 2.8 Hz), 7.91 (1H, ddd, J ) 8.7 Hz, J ) 5.4
Hz, J ) 0.6 Hz); 13C NMR (CD3OD) δ 11.4, 42.1, 48.3, 52.0,
5
2
2
108.1 (d, J C,F ) 25.2 Hz), 118.4 (d, J C,F ) 26.2 Hz), 124.7 (d,
4J C,F ) 5.0 Hz), 127.6 (d, J C,F ) 10.1 Hz), 131.3 (d, J C,F ) 9.0
3
3
3
(2H, br t, J ) 7.2 Hz), 2.62 (3H, s), 3.09 (3H, br s), 3.94 (2H,
1
3
3
3
Hz), 142.2, 144.7, 159.6, 162.0 (d, J C,F ) 246.8 Hz), 167.3.
br t, J ) 7.2 Hz), 7.02 (1H, t, J ) 7.2 Hz), 7.18 (2H, d, J )
3
Anal. (C16H19N4SOF) C, H, N.
7.2 Hz), 7.32 (2H, t, J ) 7.2 Hz), rotamer B δ 1.93 (2H, br q,
9-H yd r oxy-2-(4-m et h ylp ip er a zin -1-yl)t h ia zolo[5,4-b]-
qu in olin e, 7a : white solid (95%); mp 167-8 °C; IR (CHCl3) ν
3J ) 7.2 Hz), 2.22 (6H, s), 2.39 (2H, br t, 3J ) 7.2 Hz), 2.62
3
(3H, s), 3.48 (3H, br s), 3.54 (2H, br t, J ) 7.2 Hz), 7.02 (1H,
3660, 3400, 1600, 1550, 1450 cm-1; H NMR (CDCl3) δ 2.39
t, 3J ) 7.2 Hz), 7.18 (2H, 3J ) 7.2 Hz), 7.32 (2H, t, 3J ) 7.2
Hz); 13C NMR (CDCl3) rotamer A δ 17.0, 26.8, 34.9, 45.2, 49.3,
56.7, 117.3, 118.2, 122.5, 129.3, 141.2, 143.4, 153.5, 165.2,
rotamer B δ 17.1, 24.8, 37.9, 45.2, 47.0, 56.7, 117.3, 118.2,
122.5, 129.3, 141.0, 142.4, 152.0, 164.8.
1
(3H, s), 2.59 (4H, t, 3J ) 5.4 Hz), 3.82 (4H, t, 3J ) 5.4 Hz),
7.59 (1H, ddd, 3J ) 8.4, 6.9 Hz, 4J ) 1.5 Hz), 7.63 (1H, ddd, 3J
4
3
4
) 8.7, 6.9 Hz, J ) 1.8 Hz), 8.00 (1H, ddd, J ) 8.7 Hz, J )
5
3
4
1.5 Hz, J ) 0.9 Hz), 8.25 (1H, ddd, J ) 8.4 Hz, J ) 1.8 Hz,
5J ) 0.9 Hz); 13C NMR (CDCl3) δ 45.9, 47.9, 54.1, 123.6, 125.3,
125.4, 126.3, 127.4, 127.9, 143.0, 144.4, 158.6, 166.4. Anal.
(C15H16N4SO) C, H, N.
Cycliza tion of 5-(Ar yla m in o)-4-[[3-(N,N-d ia lk yla m in o)-
p r op yl]ca r ba m oyl]-2-(m eth ylth io)th ia zoles to 2-(Meth -
ylth io)-9-[[3-(N,N-d ia lk yla m in o)p r op yl]a m in o]th ia zolo-
[5,4-b]qu in olin es 8-10. Gen er a l P r oced u r e. 2-(Methyl-
thio)-9-[[3-(N,N-dialkylamino)propyl]amino]thiazolo[5,4-b]quin-
9-Hydr oxy-7-m eth yl-2-(4-m eth ylpiper azin -1-yl)th iazolo-
[5,4-b]qu in olin e, 7b: white solid (82%); mp 180-1 °C; IR

Synthesis, Evaluation of Thiazolo[5,4-b]quinolines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 675
olines 8-10 were obtained following the general procedure
described previously for 9-hydroxythiazolo[5,4-b]quinolines
3a -c. The crude products were purified by flash chromatog-
raphy (CH2Cl2/CH3OH/NH4OH: 98/2/traces).
9-[[3-(N ,N -Die t h yla m in o)p r op yl]a m in o]-2-(m e t h yl-
th io)th ia zolo[5,4-b]qu in olin e, 8: colorless oil (49%); IR
edged as well as Universidad Complutense de Madrid
and Universidad de Barcelona for their NMR Service
support. R.F.-G. gratefully acknowledges the Fundacio´n
Uriach for a grant. We thank Dr. Dolores G. Ga´valos
of Pharma Mar I + D Laboratory for performing the
cytostatic results and Pilar Navarro for technical sup-
port.
(CHCl3) ν 3450, 3200, 1605, 1590 cm-1
;
1H NMR (CDCl3) δ
3
3
1.13 (6H, t, J ) 6.9 Hz), 1.93 (2H, quint, J ) 5.7 Hz), 2.70
(4H, t, 3J ) 6.9 Hz), 2.71 (2H, t, 3J ) 6.9 Hz), 2.75 (3H, s),
3
3
4.33 (1H, t, J ) 5.1 Hz), 4.35 (1H, t, J ) 5.4 Hz), 7.35 (1H,
Refer en ces
ddd, 3J ) 8.4, 6.6 Hz, 4J ) 1.2 Hz), 7.59 (1H, ddd, 3J ) 8.4, 6.6
4
3
4
(1) (a) Peacocke, A. R. In Heterocyclic Compounds: The Acridines;
Acheson, R. M., Ed.; Wiley Interscience: New York, 1973. (b)
Ledochowski, A. Ledakin-Anticancerous Medicine 1-Nitro-9-(3-
dimethylaminopropylamino)acridine dihydrochloride monohy-
drate. Mater. Med. Polon. 1976, 8, 237-251. (c) Gniazdowski,
M.; Filipsky, J .; Chorazy, M. In Antibiotics; Hahn, F. E., Ed.;
Springer Verlag: Berlin, 1979; Vol. 2, pp 275-297. (d) Denny,
W. A.; Baguley, B. C.; Cain, B. F.; Waring, M. J . In Molecular
Aspects of Anticancer Drug Action; Neidle, S., Waring, M. J .,
Eds.; MacMillan Publishing Co.: London, 1983; pp 1-34. (e)
Denny, W. A. In The Chemistry of Antitumor Agents; Wilman,
D. E. V., Ed.; Blackie: Glasgow, 1990; pp 1-29.
(2) Cain, B. F.; Atwell, G. J .; Denny, W. A. Potential Antitumor
Agents. 17. 9-Anilino-10-methylacridinium Salts. J . Med. Chem.
1976, 19, 772-777.
(3) (a) Albrecht, R. Development of Antibacterial Agents of the
Nalidixic Acid Type. Prog. Drug Res. 1977, 21, 9-104. (b)
Bouzard, D. In Recent Progress in the Chemical Synthesis of
Antibiotics: Recent Advances in the Chemistry of Quinolones;
Lukacz, G., Ohno, M., Eds.; Springer Verlag: Berlin, 1990; p
249.
(4) (a) Lednicer, D.; Mitscher, L. A. Organic Chemistry of Drug
Synthesis; J ohn Wiley: New York, 1977; Vol. 1, p 340. (b) Smith,
J . T.; Lewin, C. S. Quinolones. In Chemistry and Mechanism of
Action of the Quinolone Antibacterials; Andriole, V. T., Ed.;
Academic Press: London, 1988. (c) Mekheimer, R.; Ahmed, E.
Kh.; Khattab, A. F. A Novel Nucleophilic Substitution with
Quinoline Derivatives. Synthesis of Quinolones and Pyrazolo-
[4,3-c]quinoline Derivatives. Bull. Chem. Soc. J pn. 1993, 66,
2936-2940 and references cited herein.
Hz, J ) 1.2 Hz), 7.86 (1H, dd, J ) 8.4 Hz, J ) 1.2 Hz), 7.97
(1H, d, 3J ) 8.4 Hz); 13C NMR (CDCl3) δ 10.9, 15.1, 25.7, 44.7,
46.9, 52.7, 117.3, 121.8, 122.9, 128.3, 128.6, 142.4, 145.0, 146.6,
158.5, 163.6. Anal. (C18H24N4S2) C, H, N.
9-[[3-(N,N-Diet h yla m in o)p r op yl]a m in o]-7-m et h yl-2-
(m eth ylth io)th ia zolo[5,4-b]qu in olin e, 9: colorless oil (37%);
IR (CHCl3) ν 3450, 3200, 1605, 1590 cm-1; 1H NMR (CDCl3) δ
3
3
1.16 (6H, t, J ) 7.2 Hz), 2.25 (2H, quint, J ) 5.7 Hz), 2.67
3
3
(3H, s), 2.80 (3H, s), 3.05 (4H, q, J ) 7.2 Hz), 3.06 (4H, q, J
3
3
) 7.2 Hz), 4.54 (1H, t, J ) 7.2 Hz), 7.42 (1H, d, J ) 8.7 Hz),
3
7.74 (1H, d, J ) 8.7 Hz), 8.17 (1H, br s); 13C NMR (CDCl3) δ
10.9, 15.2, 21.7, 25.7, 44.7, 47.1, 51.2, 121.4, 124.4, 125.1, 127.9,
130.2, 142.5, 145.0, 146.0, 157.6, 162.4. Anal. (C19H26N4S2)
C, H, N.
9-[N-Meth yl[3-(N′,N′-d im eth yla m in o)p r op yl]a m in o]-2-
(m eth ylth io)th iazolo[5,4-b]qu in olin e, 10: colorless oil (39%);
1
IR (CHCl3) ν 1605, 1580 cm-1; H NMR (CDCl3) δ 1.82 (2H,
quint, 3J ) 7.5 Hz), 2.15 (6H, s), 2.33 (2H, t, 3J ) 7.5 Hz), 2.78
3
(3H, s), 3.27 (3H, s), 3.73 (2H, t, J ) 7.5 Hz), 7.47 (1H, ddd,
4
3
3J ) 8.1, 6.9 Hz, J ) 1.2 Hz), 7.63 (1H, ddd, J ) 8.1, 6.9 Hz,
4J ) 1.2 Hz), 7.83 (1H, dd, 3J ) 8.1 Hz, 4J ) 1.2 Hz), 8.21 (1H,
3
4
dd, J ) 8.1 Hz, J ) 1.2 Hz); 13C NMR (CDCl3) δ 15.1, 26.2,
43.1, 45.3, 54.5, 57.1, 123.5, 124.2, 125.2, 128.2, 128.5, 137.7,
147.1, 147.2, 162.9, 164.0. Anal. (C17H22N4S2) C, H, N.
An tin eop la stic Bioa ssa ys. Four solutions of each sample
at different concentrations (20, 10, 5, and 2.5 µg/mL) were used
to perform the cytotoxicity bioassays for compounds 3a -c,
5a ,b, 7a -c, and 18b. Four 10-fold diluted additional solutions
were used for compounds 5c, 6a -c, 8-10, 18a -c. The first
solution was prepared by dilution of 1 mg of sample in a
mixture of dimethyl sulfoxide (100 µL), methanol (450 µL), and
acetone (450 µL). Additional solutions were obtained by
successive dilutions up to the required final concentrations.
Aliquots of 20 µL of each of the four solutions were added to
cultures, and the methanol and acetone were evaporated in a
sterile cabin of laminar flow at room temperature. The in vitro
antitumor activity was screened using an adapted procedure
of the method described by Bergeron et al.54 against three cell
lines: a suspension culture of a lymphoid neoplasm from
DBA/2 mouse (P-388), a monolayer culture of the human lung
carcinoma (A-549), and a monolayer culture of the human
colon carcinoma (HT-29). Cells were maintained in exponen-
tial phase of growth in Eagle’s minimum essential medium
(EMEM) which was supplemented with 5% fetal calf serum
(FCS), a 10-2 M solution of sodium bicarbonate, a mixture of
0.1 g/L penicillin G and 0.1 g/L streptomycin sulfate, Earle’s
balanced salts, and 2.0 mM L-glutamine.
Cells were seeded into 16 mm wells at 1 × 104 (P-388) or 2
× 104 (A-549 and HT-29) cells/well in 1 mL aliquots of EMEM
5% FCS containing the samples at different concentrations
(vide supra). In each case, a separate set of cultures without
drugs was seeded as control of growth to ensure that cells
remained in the exponential phase of growth. All determina-
tions were carried out in duplicate. After 3 days of incubation
at 37 °C, 10% CO2 in a 98% humid atmosphere, cells were fixed
with 0.4% formalin and stained with 0.1% crystal violet. The
results of these assays were used to obtain the dose-response
curves from which IC50 (µM) values were determined. An IC50
value represents the concentration (µM) of the sample which
produces a 50% cell growth inhibition.
(5) (a) Ridgway, M. H.; Waters, M. D.; Peel, E. M.; Ellis, P. G.
Tetrazolyloxodihydroquinoline Carboxamides. Ger. Offen. 2,407,-
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Ackn owledgm en t. Financial support from the Comi-
sio´n Interministerial para la Ciencia y la Tecnolog´ıa
(CICYT Grant No. PB90-0043) is gratefully acknowl-

676 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
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(45) Results have been quoted as IC50 values in µM units. IC50 values
stand for the concentration of sample which inhibits 50% of
normal cell culture growth in the exponential phase.
(46) Fig. P and P.Fit. Fig. P Software Corp., Cambridge, U.K., version
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(47) Two exceptions to this relationship can be considered as fol-
lows: compare IC50 ) 3.2 µM of 6b to IC50 ) 5.0 µM of 6c (for
HT-29 cell line) and IC50 ) 5.3 µM of 18a to IC50 ) 7.4 µM of
18c (for P-388 cell line).
(48) IC50 data (µM) against lymphoid neoplasm P-388 cell line in
culture have been used as comparative results.
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