Synthesis and blood-schizontocidal antimalarial activities of 2-substituted/2,5-disubstituted-8-quinolinamines and some of their amino acid conjugates

Article abstract of DOI:10.1016/j.bmc.2003.12.029

Thirteen new analogues (32-40, 45-48) of recently discovered potent blood-schizontocidal antimalarial agent, 2-tert-butylprimaquine (2) are synthesized and evaluated for in vivo antimalarial activities against drug-sensitive P. berghei strain and multi-drug resistant P. yoelii nigeriensis strain. Two of the amino acid conjugates (47-48) have exhibited potent antimalarial activities similar to that of 2 against both drug-sensitive and multi-drug resistant strains.

Full text of DOI:10.1016/j.bmc.2003.12.029

Bioorganic & Medicinal Chemistry 12 (2004) 1003–1010
Synthesis and blood-schizontocidal antimalarial activities of
2-substituted/2,5-disubstituted-8-quinolinamines and some of their
amino acid conjugates§
Meenakshi Jain, Suryanarayana Vangapandu,y Sandeep Sachdeva and Rahul Jain*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar,
Punjab 160 062, India
Received 4 November 2003;accepted 11 December 2003
Abstract—Thirteen new analogues (32–40, 45–48) of recently discovered potent blood-schizontocidal antimalarial agent, 2-tert-
butylprimaquine (2) are synthesized and evaluated for in vivo antimalarial activities against drug-sensitive P. berghei strain and
multi-drug resistant P. yoelii nigeriensis strain. Two of the amino acid conjugates (47–48) have exhibited potent antimalarial activ-
ities similar to that of 2 against both drug-sensitive and multi-drug resistant strains.
# 2004 Elsevier Ltd. All rights reserved.
1. Introduction
and can’t be used to cure infections caused by P. falci-
parum.2 Usefulness of 1 is also restricted by toxic side
effects including hemolytic lesions (caused by methe-
moglobin production), pronounced in the patients defi-
cient in glucose-6-phosphate dehydrogenase. Our
research efforts are directed towards improving blood-
schizontocidal antimalarial activity of primaquine, and
at the same time reducing the toxic manifestations that
are traditionally associated with it. In this direction, we
have recently reported that the placement of a bulky
metabolically stable tert-butyl group at the C-2 position
of quinoline ring in 1 results in tremendous improve-
ment in the blood-schizontocidal antimalarial activity.3
Antimalarial compound, 2-tert-butylprimaquine (2)
(Fig. 1) exhibits potent in vivo antimalarial activities
against both drug-sensitive strain (P. berghei), and
multi-drug resistant strain (P. yoelii nigeriensis), and
thus is a powerful blood-schizontocide. Furthermore,
analogue 2 is discovered to be the first 8-quinolinamine
completely devoid of methemoglobin (MetHb) toxicity
associated with 1. We had proposed that the extremely
encouraging and remarkable antimalarial activities of
the analogue 2 are emanated by blocking of a putative
unwarranted metabolic degradation pathway of the
primaquine at the C-2 position of the quinoline ring.3
The most logical extension of this spectacular finding is
to further explore the optimum size requirement of alkyl
group at the C-2 position and other substituents in pri-
maquine. Herein, we describe synthesis and antimalarial
activities of nine additional 2-substituted and 2,5-di-
Malaria, the ancient mosquito-borne disease that was
rolled back by medical advances in the mid-20th cen-
tury, is making a deadly comeback, with 600 million
estimated clinical cases and approximately 3 million deaths
per year.1 Nearly all fatalities are caused by Plasmodium
falciparum;one of the four species responsible for caus-
ing human malaria. The parasite’s resistance to con-
ventional antimalarial drugs such as chloroquine, the
cheapest and most effective anti-malarial since the 1950s
is growing at an alarming rate. Therefore, a re-look at
the promising existing drugs that are effective against
resistant strain and new efficient drugs are urgently
needed.
2. Results and discussion
Primaquine (1) is known to be active against more of
the life cycle stages of plasmodia than any other class
of antimalarial drugs, but has minimal suppressive
activity;that is, is ineffective as blood-schizontocide,
Keywords: Malaria;8-Quinolinamines;2- tert-Butylprimaquine;Blood-
schizontocides.
* Corresponding author. Tel.: +91-172-221-4682;fax: +91-172-221-
4692;e-mail: rahuljain@niper.ac.in
Present address: Research Institute of Pharmaceutical Sciences,
University of Mississippi, University, MS 38677, USA.
§NIPER communication no. 245.
y
0968-0896/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.12.029

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M. Jain et al. / Bioorg. Med. Chem. 12 (2004) 1003–1010
nitroquinolines (5–13), which were conveniently sepa-
rated by column chromatography. The latter com-
pounds (5–13) were converted to the requisite 2-
substituted/2,5-disubstituted N8-(4-amino-1-methylbu-
tyl)-6-methoxy-8-quinolinamines (32–40) in three steps
following previously published procedure (Scheme 1).6
On the other hand, 2-tert-butylprimaquine (2) synthe-
sized using procedure reported earlier,3 upon condensa-
tion reaction with N-carbobenzyloxy (Z) protected
l-amino acids in the presence of 1,3-dicyclohexyl-
carbodiimide (DCC) in CH2Cl2 for 4 h gave the required
N8-(4-amino-1-methylbutyl)-2-tert-butyl-6-methoxy-8-
quinolinamine-Z-amino acid conjugates (41–44) in
excellent yields. Hydrogenolysis of the latter com-
pounds (41–44) at ambient temperature using 10% Pd-
C catalyst in the presence of H2 gas proceeded smoothly
to produce the free amino acid conjugates that upon
treatment with ethereal hydrogen chloride solution pro-
vided the N8-(4-amino-1-methylbutyl)-2-tert-butyl-6-
methoxy-8-quinolinamine-amino acid conjugates (45–
48) as their hydrochloride salts (Scheme 2).
Figure 1.
substituted primaquine analogues (32–40) bearing other
metabolically stable groups.
It is known that approximately 35–83% of primaquine
gets metabolized to 4-(6-methoxy-quinolin-8-ylamino)-
pentanoic acid in a primate model.4 We have recently
proposed that attachment of an amino acid residue may
serve to protect the primary amino function of 1 against
the aforementioned metabolic process.5 This study
demonstrates that a careful selection of amino acids and
their attachment at the primary amino group led to a
substantially increase in the antimalarial activities of 8-
quinolinamines.5 Keeping these observations in mind,
the present work also reports synthesis and antimalarial
activity evaluation of four amino acid conjugates (45–
48) of 2-tert-butylprimaquine (2).
4. Biological activity
The target compounds were evaluated for in vivo blood-
schizontocidal antimalarial activity against P. berghei
(sensitive strain) in a rodent model (Table 1). The
details of the biological procedure are reported else-
where.7 Briefly;testing of synthesized analogues was
conducted at various concentrations, orally, in mice (6
mice per group). The concentrations tested were 100, 50,
25 and 10 mg/kg/dayꢀ4 (oral). The compounds were
administered on days 0–3 post infection. The results for
the synthesized analogues were compared to a positive
3. Chemistry
Commercially available 6-methoxy-8-nitroquinoline (3)
and 5,6-dimethoxy-8-nitroquinoline (4) upon direct
ring-alkylation via a silver catalyzed radical oxidative
decarboxylation of appropriate alkylcarboxylic acid by
ammonium persulfate in CH3CN and 10%H2SO4 effi-
ciently produced a mixture of mono and dialkylated 8-
Scheme 1. Reagents and conditions: (i) R1CO2H, AgNO3, (NH4)2S2O8, 10% H2SO4, CH3CN, 70 ꢁC;(ii) Raney Ni, EtOH, H 2, 45 psi, 45 min;
ꢁ
.
(iii) 2-(4-bromopentyl)-1,3-isoindolinedione, Et3N, 120 C, 24 h;(iv) NH NH2 H2O, EtOH, reflux, 8 h.
2
Scheme 2. Reagents and conditions: (i) Z-L-R2-OH, DCC, CH2Cl2, rt;(ii) H 2/Pd-C, 1 h, rt.

M. Jain et al. / Bioorg. Med. Chem. 12 (2004) 1003–1010
1005
Table 1. In vivo blood-schizontocidal antimalarial activity of the N8-(4-amino-1-methylbutyl)-2-substituted/2,5-disubstituted-6-methoxy-8-quino-
linamines (32–40) and 2-tert-butylprimaquine conjugates (45–48) against P. berghei infection in mice (6 mice per group)
S. No.
R
R1
R2
Dose
(mg/kg/dayꢀ4, oral)
10
25
50
100
32
33
34
35
36
37
38
39
40
45
46
47
48
H
CH(CH3)2
H
c-C5H9
H
c-C6H11
OCH3
OCH3
OCH3
—
CH(CH3)2
CH(CH3)2
c-C5H9
c-C5H9
c-C6H11
c-C6H11
CH(CH3)2
C(CH3)3
c-C6H11
—
—
—
—
—
—
—
—
—
—
CH3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
(3/6) Active
—
(6/6) Curative
(0/6) Inactive
(0/6) Inactive
(0/6) Inactive
(0/6) Inactive
(0/6) Inactive
(2/6) Active
—
—
—
—
—
—
—
(3/6) Active
—
—
—
—
—
—
(0/6) Inactive
(6/6) Curative
(0/6) Inactive
(6/6) Curative
(6/6) Curative
(6/6) Curative
(0/6) Inactive
(4/6) Active
—
(6/6) Curative
(6/6) Curative
(6/6) Curative
—
—
—
—
—
—
CH(CH3)2
(CH2)3NH2
(CH2)4NH2
(2/6) Active
(4/6) Active
(4/6) Active
—
(6/6) Curative
(6/6) Curative
(6/6) Curative
—
—
2-tert-Butylprimaquine (2)
Primaquine
The term ‘curative’ indicates complete elimination of malaria parasites, and animals survive up to day D+60. The term ‘active’ indicates that treated
animals show negative parasitaemia up to D+7. However, by D+60, some mice die, and some survive with complete elimination of parasitaemia as
indicated by numbers given in parentheses. The term ‘inactive’ indicates that the treated animals show positive parasitaemia either on D+4 or D+7
and usually die by D+14.
control group of mice treated with chloroquine at a
suppressive dose of 10 mg/kg/dayꢀ4 (oral). The results
were also compared to a negative control group of mice
where no treatment for the infection was administered,
and in this case 100% mortality is observed within 6–8
days, with a mean survival time of 6.2 days.
(47) and lysine adduct (48) exhibited potent antimalarial
activities, and have produced partial cures at the lowest
tested dosage of 10 mg/kg. Although analogue 48 was
equi-potent to 2-tert-butylprimaquine (2), none of the
synthesized amino acid conjugates were found superior
to it.
All of the 2-substituted/2,5-disubstituted N8-(4-amino-
1-methylbutyl)-6-methoxy-8-quinolinamines (32–40) were
found to be less effective compared to analogue 2 in the
P. berghei test. The most effective compound 32 [R=H,
R1=CH(CH3)2] produced 100% cures at the pre-
liminary tested dose of 100 mg/kg, but exhibited only
partial cures at 50 mg/kg. The observation of insignif-
icant activity in the synthesized derivatives suggests that
the tert-butyl group placed at C-2 position of the quin-
oline ring in primaquine is optimal for superior anti-
malarial activity. Likewise, placement of an additional
alkyl substitution at C-5 position of the quinoline ring
(2,5-dialkylated analogues 33, 35 and 37) led to dimin-
ished antimalarial activity. Finally, placement of 5-
methoxy group in the quinoline ring (analogues 38–40)
resulted in compounds with complete loss of anti-
malarial activity. To our surprise, placement of an
additional methoxy group at the C-5 position (analogue
38) in 2-tert-butylprimaquine (2) also resulted in drastic
reduction in antimalarial activity. The complete loss of
activity in analogue 2 by virtue of an additional meth-
oxy group in the ring clearly indicates that strategic
positioning of 6-methoxy and 2-tert-butyl groups is
required for superior antimalarial activities.
Compounds exhibiting activity at 10 mg/kg/day were
further selected for evaluation of antimalarial efficacy in
P. yoelii nigeriensis (multi-drug resistant strain) using
protocol similar to that for P. berghei test, and results
are summarized in Table 2. Along the same lines with
the results obtained for P. berghei test model, analogues
47 and 48 produced partial cures at the preliminary
tested dose of 100 mg/kg. Analogue 48 showed anti-
malarial activity similar to that of 2-tert-butylprima-
quine (2) and cured 2/6 mice at a dose of 50 mg/kg.
Table 2. In vivo blood-schizontocidal antimalarial activity of the 2-
tert-butylprimaquine conjugates (47–48) against multi-drug resistant
P. yoelii nigeriensis infection in mice (6 mice per group)
S. No.
R2
Dose
(mg/kg/dayꢀ4, oral)
50
100
47
48
(CH2)3NH2 (0/6) Inactive (3/6) Active
(CH2)4NH2 (2/6) Active (4/6) Active
(4/6) Active (6/6) Curative
2-tert-Butylprimaquine (2)
Primaquine
—
(0/6) Inactive
As observed by us earlier in the cases involving various
5-alkoxyprimaquine analogues,5 valine adduct (46) of
analogue 2 also did not show any antimalarial activity;
whereas, alanine conjugate (45) exhibited 100% cures
at 100 mg/kg, but was only partially curative at the next
tested dose of 50 mg/kg. In contrast, ornithine adduct
The term ‘curative’ indicates complete elimination of malaria para-
sites, and animals survive up to day D+60. The term ‘active’ indicates
that treated animals show negative parasitaemia up to D+7. How-
ever, by D+60, some mice die, and some survive with complete elim-
ination of parasitaemia as indicated by numbers given in parentheses.
The term ‘inactive’ indicates that the treated animals show positive
parasitaemia either on D+4 or D+7 and usually die by D+14.

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M. Jain et al. / Bioorg. Med. Chem. 12 (2004) 1003–1010
5. Conclusions
(230–400 mesh) afforded 2-substituted/2,5-disubstituted-
8-nitroquinolines (5–13).
In summary, to further explore the most suitable alkyl
group at the C-2 position in primaquine, we have syn-
thesized additional analogues of the recently discovered
2-tert-butylprimaquine (2). The results of this study
clearly established that the potent antimalarial activity
displayed by 2 is attributed to the incorporation of 2-
tert-butyl group in primaquine, and its replacement with
other metabolically stable groups like adamantyl, iso-
propyl, cyclohexyl and cyclopentyl results in reduced
antimalarial activity. Furthermore, in agreement with
our earlier observations with 5-alkoxyprimaquines,
lysine and ornithine conjugated derivatives (47–48)
exhibited promising antimalarial effects similar to that
of 2 against drug-sensitive and multi-drug-resistant
malaria strains. However, incorporation of these amino
acids failed to enhance the bio-efficacy of analogue 2.
Our efforts are currently directed towards exploration
of other cationic l- and d-amino acids seeking further
enhancement in the antimalarial activities of 2, and
results of this study will be published shortly.
6.1.1. 2-Isopropyl-6-methoxy-8-nitroquinoline (5).ꢂY1 ield:
;
1H
47%;mp 73–74 ꢁC;IR (KBr) 1540, 1388 cm
NMR (CDCl3) d 8.01 (d, 1H, J=8.6 Hz), 7.60 (s, 1H),
7.40 (d, 1H, J=8.6 Hz), 7.26 (s, 1H), 3.95 (s, 3H), 3.19
(m, 1H), 1.43 (m, 6H);EIMS m/z 246 (M+);analysis for
C13H14N2O3 (246.3), calcd, C, 63.40;H, 5.73;N, 11.38;
found, C, 63.41;H, 5.79;N, 11.65.
6.1.2. 2,5-Diisopropyl-6-methoxy-8-nitroquinoline (6).
1
Yield: 12%;oil;IR (KBr) 1545, 1395 cm ꢂ1; H NMR
(CDCl3) d 8.09 (d, 1H, J=8.4 Hz), 7.47 (d, 1H, J=8.4
Hz), 7.19 (s, 1H), 3.99 (s, 3H), 3.22 (m, 2H), 1.52 (m,
6H), 1.48 (m, 6H);EIMS m/z 288 (M+);analysis for
C16H20N2O3 (288.3), calcd, C, 66.65;H, 6.99;N, 9.72;
found, C, 66.45;H, 6.74;N, 9.78.
6.1.3. 2-Cyclopentyl-6-methoxy-8-nitroquinoline (ꢂ71).
Yield: 52%;mp 85–86 ꢁC;IR (KBr) 1535, 1215 cm
;
1H NMR (CDCl3) d 8.10 (d, 1H, J=8.4 Hz), 7.63 (s,
1H), 7.45 (d, 1H, J=8.4 Hz), 7.21 (s, 1H), 3.98 (s, 3H),
3.15 (m, 1H), 1.64 (m, 8H);EIMS m/z 272 (M+);ana-
lysis for C15H16N2O3 (272.3), calcd, C, 66.16;H, 5.92;
N, 10.29;found, C, 66.44;H, 5.73;N, 10.37.
6. Experimental
Melting points were recorded on Mettler DSC 851 or
capillary melting point apparatus and are uncorrected.
1H spectra were recorded on 300 MHz Bruker FT-NMR
(Avance DPX300) spectrometer using tetramethylsilane
as internal standard and the chemical shifts are reported
in d units. Mass spectra were recorded on either GCMS
(Shimadzu QP 5000 spectrometer) auto sampler/direct
injection (EI/CI) or HRMS (Finnigan Mat LCQ spec-
trometer) (APCI/ESI). Elemental analyses were recorded
on Elementar Vario EL spectrometer. All chromato-
graphic purification was performed with silica gel 60 (230–
400 mesh), whereas all TLC (silica gel) development was
6.1.4. 2,5-Dicyclopentyl-6-methoxy-8-nitroquinoline (8).
1
Yield: 10%;oil;IR (KBr) 1545, 1388 cm ꢂ1; H NMR
(CDCl3) d 8.09 (d, 1H, J=8.1 Hz), 7.47 (d, 1H, J=8.1
Hz), 7.17 (s, 1H), 3.98 (s, 3H), 2.82 (m, 2H), 1.74 (m,
16H);EIMS m/z 340 (M+);analysis for C 20H24N2O3
(340.4), calcd, C, 70.56;H, 7.11;N, 8.23;found, C,
70.44;H, 7.07;N, 8.23.
6.1.5.
2-Cyclohexyl-6-methoxy-8-nitroquinoline
(ꢂ91).
Yield: 43%;mp 88–89 ꢁC;IR (KBr) 1533, 1386 cm
;
1H NMR (CDCl3) d 8.14 (d, 1H, J=8.4 Hz), 7.67 (s,
1H), 7.41 (d, 1H, J=8.4 Hz), 7.23 (s, 1H), 3.99 (s, 3H),
2.82 (m, 1H), 1.67 (m, 10H);EIMS m/z 286 (M+);ana-
lysis for C16H18N2O3 (286.3), calcd, C, 67.12;H, 6.34;
N, 9.78;found, C, 66.98;H, 6.52;N, 9.63.
performed on silica gel coated (Merck Kiesel 60 F254
,
0.2 mm thickness) sheets. All chemicals were purchased
from Aldrich Chemical Ltd (Milwaukee, WI, USA).
Solvents used for the chemical synthesis acquired from
commercial sources were of analytical grade, and were
used without further purification unless otherwise stated.
6.1.6. 2,5-Dicyclohexyl-6-methoxy-8-nitroquinoline (10).
1
Yield: 11%;oil;IR (KBr) 1537, 1382 cm ꢂ1; H NMR
(CDCl3) d 8.09 (d, 1H, J=8.2 Hz), 7.49 (d, 1H, J=8.2
Hz), 7.12 (s, 1H), 3.94 (s, 3H), 2.87 (m, 2H), 1.77 (m,
20H);EIMS m/z 368 (M+);analysis for C 22H28N2O3
(368.5), calcd, C, 71.71;H, 7.66;N, 7.60;found, C,
72.04;H, 7.59;N, 7.79.
6.1. General method for the synthesis of 2-substituted/
2,5-disubstituted-8-nitroquinolines (5–13)
A solution of 6-methoxy-8-nitroquinoline (3, 1 mmol)
or 5,6-dimethoxy-8-nitroquinoline (4,
1 mmol) in
CH3CN (5 mL) was heated to 70 ꢁC. Silver nitrate (0.6
mmol), requisite alkylcarboxylic acid (2.5 mmol), and
10% H2SO4 (10 mL) was added to the reaction mixture.
A freshly prepared solution of ammonium persulfate (3
mmol) in water (10 mL) was added drop wise during 10
min. The heating source was removed and reaction
proceeded with the evolution of carbon dioxide. After
10 min, reaction mixture was poured onto ice, and made
alkaline by adding 30% NH4OH solution. Extracted
with CHCl3 (4ꢀ50 mL), and combined extracts were
washed with NaCl solution (2ꢀ10 mL). Dried over
Na2SO4, and solvent removed in vacuo to afford oil,
which upon column chromatography over silica gel
6.1.7. 2-Isopropyl-5,6-dimethoxy-8-nitroquinoline (1ꢂ11).
Yield: 55%;mp 91–92 ꢁC;IR (KBr) 1565, 1340 cm
;
1H NMR (CDCl3) d 7.87 (d, 1H, J=8.8 Hz), 7.65 (s,
1H), 6.86 (d, 1H, J=8.8 Hz), 4.08 (s, 3H), 4.02 (s, 3H),
3.12 (m, 1H), 1.25 (m, 6H);EIMS m/z 276 (M+);ana-
lysis for C14H16N2O4 (276.3), calcd, C, 60.86;H, 5.84;
N, 10.14;found, C, 60.77;H, 5.69;N, 9.98.
6.1.8. 2-tert-Butyl-5,6-dimethoxy-8-nitroquinoline (1ꢂ21).
Yield: 65%;mp 79–80 ꢁC;IR (KBr) 1528, 1349 cm
;
1H NMR (CDCl3) d 8.05 (d, 1H, J=8.9 Hz), 7.89 (s,
1H), 7.60 (d, 1H, J=8.9 Hz), 4.07 (s, 3H), 4.02 (s, 3H),

M. Jain et al. / Bioorg. Med. Chem. 12 (2004) 1003–1010
1007
1.42 (s, 9H);ESIMS m/z 291 (M+1);analysis for
C15H18N2O4 (290.3), calcd, C, 60.06;H, 6.25;N, 9.65;
found, C, 60.25;H, 6.59;N, 9.79.
6.2.6. 2,5-Dicyclohexyl-6-methoxy-8-quinꢂol1inamine (19).
Yield: 88%;oil;IR (KBr) 3030 cm
1H NMR
;
(CDCl3) d 7.95 (d, 1H, J=8.5 Hz), 7.28 (d, 1H, J=8.5
Hz), 6.58 (s, 1H), 5.14 (bs, 2H), 3.84 (s, 3H) 3.23 (m,
2H), 1.77 (m, 20H);EIMS m/z 338 (M+);analysis for
C22H30N2O (338.5), calcd, C, 78.06;H, 8.93;N, 8.28;
found, C, 78.32;H, 9.05;N, 7.99.
6.1.9. 2-Cyclohexyl-5,6-dimethoxy-8-nitroquinoline (1ꢂ31).
Yield: 57%;mp 84–85 ꢁC;IR (KBr) 1540, 1375 cm
;
1H NMR (CDCl3) d 7.94 (d, 1H, J=8.6 Hz), 7.75 (s,
1H), 6.93 (d, 1H, J=8.6 Hz), 3.98 (s, 3H), 3.97 (s, 3H),
2.92 (m, 1H), 1.25 (s, 10H);EIMS m/z 316 (M+);ana-
lysis for C17H20N2O4 (316.3), calcd, C, 64.54;H, 6.37;
N, 8.86;found, C, 64.30;H, 6.39;N, 8.88.
6.2.7. 2-Isopropyl-5,6-dimethoxy-8-quinoꢂli1namine (20).
Yield: 93%;oil;IR (KBr) 3355 cm
;
1H NMR
(CDCl3) d 7.70 (d, 1H, J=9.2 Hz), 7.23 (d, 1H, J=9.2
Hz), 6.82 (s, 1H), 5.71 (bs, 2H), 4.14 (s, 3H), 4.12 (s,
3H), 3.10 (m, 1H), 1.20 (m, 6H);EIMS m/z 246 (M+);
analysis for C14H18N2O2 (246.3), calcd, C, 68.27;H,
7.37;N, 11.37;found, C, 68.53;H, 7.05;N, 11.44.
6.2. General method for the synthesis of 2-substituted/
2,5-disubstituted-6-methoxy-8-quinolinamines (14–22)
A solution of 2-substituted/2,5-disubstituted-6-meth-
oxy-8-nitroquinoline (5–13, 5 mmol) in 95% ethyl alco-
hol (15 mL) was hydrogenated over wet raney nickel (T1
grade) at 45 psi in a parr hydrogenator for 45 min.
Catalyst was removed by filtration, and filtrate was
evaporated under vacuum to afford 2-substituted/2,5-
disubstituted-6-methoxy-8-quinolinamine (14–22) as
dark colored oil.
6.2.8. 2-tert-Butyl-5,6-dimethoxy-8-quinolinamine (21).
ꢂ1
Yield: 97%;oil;IR (KBr) 3461 cm
;
1H NMR
(CDCl3) d 8.32 (d, 1H, J=8.85 Hz), 7.52 (d, 1H,
J=8.85 Hz), 6.81 (s, 1H), 5.1 (bs, 2H), 3.95 (s, 3H), 3.88
(s, 3H), 1.51 (s, 9H);ESIMS m/z 261 (M+1);analysis
for C15H20N2O2 (260.3), calcd, C, 69.20;H, 7.74;N,
10.76;found, C, 68.97;H, 7.73;N, 10.55.
6.2.1. 2-Isopropyl-6-methoxy-8-quinolinamine (14). Yield:
95%;oil;IR (KBr) 3330 cm ꢂ1; 1H NMR (CDCl3) d 7.84
(d, 1H, J=8.6 Hz), 7.41 (d, 1H, J=8.6 Hz), 6.54 (s,
1H), 6.43 (s, 1H), 5.13 (bs, 2H), 4.22 (s, 3H), 3.07 (m,
1H), 1.39 (m, 6H);EIMS m/z 216 (M+);analysis for
C13H16N2O (216.3), calcd, C, 72.19;H, 7.46;N, 12.95;
found, C, 72.12;H, 7.37;N, 13.09.
6.2.9. 2-Cyclohexyl-5,6-dimethoxy-8-quinꢂol1inamine (22).
Yield: 80%;oil;IR (KBr) 3230 cm
;
1H NMR
(CDCl3) d 8.33 (d, 1H, J=9.0 Hz), 7.51 (d, 1H, J=9.0
Hz), 6.81 (s, 1H), 5.17 (bs, 2H), 3.95 (s, 3H), 3.88 (s,
3H), 3.1 (m, 1H), 1.45 (m, 10H);EIMS m/z 286 (M+);
analysis for C17H22N2O2 (286.4), calcd, C, 71.30;H,
7.74;N, 9.78;found, C, 71.55;H, 7.79;N, 10.12.
6.2.2. 2,5-Diisopropyl-6-methoxy-8-quinolinamine (15).
ꢂ1
6.3. General method for the synthesis of 2-[4-(2-sub-
stituted/2,5-disubstituted-6-methoxy-8-quinolylamino)-
pentyl]-1,3-isoindolinediones (23–31)
Yield: 88%;oil;IR (KBr) 3333 cm
;
1H NMR
(CDCl3) d 7.67 (d, 1H, J=8.5 Hz ), 6.90 (d, 1H, J=8.5
Hz), 6.77 (s, 1H), 5.17 (bs, 2H), 4.15 (s, 3H), 3.17 (m,
2H), 1.42 (m, 6H), 1.37 (m, 6H);EIMS m/z 258 (M+);
analysis for C16H22N2O (258.4), calcd, C, 74.38;H,
8.58;N, 10.84;found, C, 74.37;H, 8.79;N, 10.57.
A mixture of 2-substituted/2,5-disubstituted-6-methoxy-
8-quinolinamine (14–22, 4 mmol), 2-(4-bromopentyl)-
1,3-isoindolinedione (4 mmol) and triethylamine
(4 mmol) was heated at 120 ꢁC with stirring for 4 h.
An additional quantity of 2-(4-bromopentyl)-1,3-iso-
indolinedione (6 mmol) and triethylamine (4 mmol) was
added, and stirring continued with heating for another
4 h. A third aliquot of 2-(4-bromopentyl)-1,3-isoindoline-
dione (4 mmol) and triethylamine (4 mmol) was added,
and the reaction mixture stirred at 120 ꢁC for addi-
tional 16 h. The dark brown reaction mixture was
diluted with ethyl acetate (75 mL) and filtered. The fil-
trate was basified with 2N NaOH solution and extrac-
ted with ethyl acetate (3ꢀ50 mL). The combined
extracts were washed with water (15 mL), dried over
Na2SO4, and concentrated to afford dark colored resi-
due. Flash column chromatography on silica gel using
EtOAc/hexanes (20:80) provided 2-[4-(2-substituted/
2,5-disubstituted-6-methoxy-8-quinolylamino)pentyl]-
1,3-isoindolinediones (23–31) as colorless or pale yellow
viscous oil.
6.2.3. 2-Cyclopentyl-6-methoxy-8-quinolinamine (16).
1
Yield: 92%;oil;IR (KBr) 2958, 2928 cm ꢂ1; H NMR
(CDCl3) d 7.75 (d, 1H, J=8.4 Hz), 6.88 (d, 1H, J=8.4
Hz), 6.60 (s, 1H), 6.48 (s, 1H), 5.09 (bs, 2H), 3.89 (s,
3H), 3.57 (m, 1H), 1.88 (m, 8H);EIMS m/z 242 (M+);
analysis for C15H18N2O (242.3), calcd, C, 74.35;H,
7.49;N, 11.56;found, C, 74.39;H, 7.67;N, 11.88.
6.2.4. 2,5-Dicyclopentyl-6-methoxy-8-quinꢂo1linamine (17).
;
1H NMR
Yield: 90%;oil;IR (KBr) 2930 cm
(CDCl3) d 7.92 (d, 1H, J=8.3 Hz), 7.23 (d, 1H, J=8.3
Hz), 6.57 (s, 1H), 5.09 (bs, 2H), 3.89 (s, 3H), 3.29 (m,
2H), 1.94 (m, 16H);EIMS m/z 310 (M+);analysis for
C20H26N2O (310.4), calcd, C, 77.38;H, 8.44;N, 9.02;
found, C, 77.47;H, 8.71;N, 8.79.
6.2.5. 2-Cyclohexyl-6-methoxy-8-quinolinamine (18).
1
Yield: 82%;oil;IR (KBr) 3008, 2926 cm ꢂ1; H NMR
(CDCl3) d 7.80 (d, 1H, J=8.4 Hz), 6.91 (d, 1H, J=8.4
Hz), 6.66 (s, 1H), 6.50 (s, 1H), 5.10 (bs, 2H), 3.89 (s, 3H)
3.10 (m, 1H), 1.69 (m, 10H);EIMS m/z 256 (M+);ana-
lysis for C16H20N2O (256.3), calcd, C, 74.97;H, 7.86;N,
10.93;found, C, 75.21;H, 8.03;N, 9.77.
6.3.1. 2-[4-(2-Isopropyl-6-methoxy-8-quinolylamino)pen-
tyl]-1,3-isoindolinedione (23). Yield: 73%;oil;IR (KBr)
;
3433, 1709 cmꢂ1 1H NMR (CDCl3) d 7.88 (d, 1H,
J=8.3 Hz), 7.83 (m, 4H), 7.41 (d, 1H, J=8.3 Hz), 6.27
(s, 1H), 6.24 (s, 1H), 4.81 (bs, 1H), 3.86 (s, 3H), 3.52 (m,

1008
M. Jain et al. / Bioorg. Med. Chem. 12 (2004) 1003–1010
3H), 2.93 (m, 1H), 1.70 (m, 2H), 1.46 (m, 2H), 1.32 (m,
6H), 0.98 (d, 3H, J=6.5 Hz);EIMS m/z 431(M+);
analysis for C26H29N3O3 (431.5), calcd, C, 72.37;H,
6.77;N, 9.74;found, C, 72.44;H, 6.89;N, 9.93.
70.26;H, 6.77;N, 9.10;found, C, 70.34;H, 7.05;N,
8.93.
6.3.8. 2-[4-(2-tert-Butyl-5,6-dimethoxy-8-quinolylamino)-
pentyl]-1,3-isoindolinedione (30). Yield: 66%;oil;IR
1
6.3.2. 2-[4-(2,5-Diisopropyl-6-methoxy-8-quinolylamino)-
pentyl]-1,3-isoindolinedione (24). Yield: 77%;oil;IR
(KBr) 3382, 1712 cmꢂ1; H NMR (CDCl3) d 8.20 (d,
1H, J=9.0 Hz), 7.82 (m, 4H), 7.46 (d, 1H, J=9.0 Hz),
6.38 (s, 1H), 6.02 (bs, 1H), 3.96 (s, 3H), 3.84 (s, 3H),
3.69 (t, 2H), 3.64 (m, 1H), 1.73 (m, 4H) 1.41 (s, 9H),
1.31 (d, 3H, J=6.9 Hz);ESIMS m/z 476 (M+1);ana-
lysis for C28H33N3O4 (475.6), calcd, C, 70.71;H, 6.99;
N, 8.84;found, C, 70.66;H, 6.89;N, 8.81.
1
(KBr) 3400, 1715 cmꢂ1; H NMR (CDCl3) d 8.12 (d,
1H, J=7.5 Hz), 7.80 (m, 4H), 7.35 (d, 1H, J=7.5 Hz),
6.87 (s, 1H), 4.82 (bs, 1H), 3.87 (s, 3H), 3.53 (m, 3H),
3.10 (m, 2H,), 1.73 (m, 2H), 1.49 (m, 2H), 1.39 (m, 6H),
1.32 (m, 6H), 0.98 (d, 3H, J=6.6 Hz);EIMS m/z 473
(M+);analysis for C 29H35N3O3 (473.6), calcd, C, 73.54;
H, 7.45;N, 8.87;found, C, 73.52;H, 7.49;N, 8.55.
6.3.9. 2-[4-(2-Cyclohexyl-5,6-dimethoxy-8-quinolylamino)-
pentyl]-1,3-isoindolinedione (31). Yield: 70%;oil;IR
1
6.3.3. 2-[4-(2-Cyclopentyl-6-methoxy-8-quinolylamino)-
pentyl]-1,3-isoindolinedione (25). Yield: 74%;oil;IR
;
(KBr) 1712 cmꢂ1 1H NMR (CDCl3) d 7.90 (d, 1H,
J=8.3 Hz), 7.81 (m, 4H), 7.45 (d, 1H, J=8.3 Hz), 6.33
(s, 1H), 6.28 (s, 1H), 5.12 (bs, 1H), 3.89 (s, 3H), 3.69 (m,
3H), 3.46 (m, 1H), 2.02 (m, 4H), 1.69 (m, 8H), 1.22 (d,
3H, J=6.9 Hz);EIMS m/z 457 (M+);analysis for
C28H31N3O3 (457.6), calcd, C, 73.50;H, 6.83;N, 9.18;
found, C, 73.57;H, 6.87;N, 8.91.
(KBr) 3350, 1720 cmꢂ1; H NMR (CDCl3) d 8.22 (d,
1H, J=9.2 Hz), 7.75 (m, 4H), 7.46 (d, 1H, J=9.2 Hz),
6.39 (s, 1H), 6.0 (bs, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 3.69
(t, 2H), 3.64 (m, 1H), 3.20 (m, 1H), 1.75 (m, 4H) 1.41
(m, 10H), 1.35 (d, 3H, J=6.7 Hz);EIMS m/z 501 (M+);
analysis for C30H35N3O4 (501.6), calcd, C, 71.83;H,
7.03;N, 8.38;found, C, 71.91;H, 7.38;N, 8.38.
6.4. General method for the synthesis of N8-(4-amino-1-
methylbutyl)-2-substituted/2,5-disubstituted-6-methoxy-
8-quinolinamines (32–40)
6.3.4. 2-[4-(2,5-Dicyclopentyl-6-methoxy-8-quinolylamino)-
pentyl]-1,3-isoindolinedione (26). Yield: 89%;oil;IR
(KBr) 1715 cmꢂ1
;
1H NMR (CDCl3) d 7.95 (d, 1H,
A solution of 2-[4-(2-substituted/2,5-disubstituted-6-
methoxy-8-quinolylamino)pentyl]-1,3-isoindolinedione
(23–31, 5 mmol) in 95% ethyl alcohol (25 mL), and
hydrazine hydrate (100 mmol) was heated under reflux
for 8 h. Solvent was removed under reduced pressure,
and the residue was taken up in water (25 mL), and
basified with 8N NaOH solution. Extracted with CHCl3
(4ꢀ20 mL), and washed once with water (10 mL).
Combined organic extracts were dried over Na2SO4,
and concentrated under reduced pressure to yield N8-(4-
amino-1-methylbutyl)-2-substituted/2,5-disubstituted-6-
methoxy-8-quinolinamines (32–40) as oil. Treatment
with ethereal hydrochloric acid solution provided 32–40
as their hydrochloride salts.
J=7.9 Hz), 7.85 (m, 4H), 7.27 (d, 1H, J=7.9 Hz), 6.69
(s, 1H), 5.12 (bs, 1H), 3.89 (s, 3H), 3.65 (m, 3H), 3.44
(m, 2H), 2.07 (m, 4H), 1.62 (m, 16H), 1.21 (d, 3H,
J=6.9 Hz);EIMS
m/z 525 (M+);analysis for
C33H39N3O3 (525.7), calcd, C, 75.40;H, 7.48;N, 7.99;
found, C, 75.07;H, 7.63;N, 8.11.
6.3.5. 2-[4-(2-Cyclohexyl-6-methoxy-8-quinolylamino)pen-
tyl]-1,3-isoindolinedione (27). Yield: 63%;oil;IR (KBr)
;
3387, 1713 cmꢂ1 1H NMR (CDCl3) d 7.91 (d, 1H,
J=8.3 Hz), 7.79 (m, 4H), 7.49 (d, 1H, J=8.3 Hz), 6.37
(s, 1H), 6.30 (s, 1H), 5.15 (bs, 1H), 3.89 (s, 3H), 3.68 (t,
2H), 3.32 (m, 1H), 3.18 (m, 1H), 2.22 (m, 4H), 1.50 (m,
10H), 1.10 (d, 3H, J=6.9 Hz);EIMS m/z 471 (M+);
analysis for C29H33N3O3 (471.6), calcd, C, 73.86;H,
7.05;N, 8.91;found, C, 73.52;H, 7.13;N, 8.63.
6.4.1. N8-(4-Amino-1-methylbutyl)-2-isopropyl-6-methoxy-
.
8-quinolinamine 2HCl (32). Yield: 61%;mp (salt) 99–
102 ꢁC (dec);IR (KBr) 3422 cm ꢂ1; H NMR (free base,
1
6.3.6. 2-[4-(2,5-Dicyclohexyl-6-methoxy-8-quinolylamino)-
pentyl]-1,3-isoindolinedione (28). Yield: 88%;oil;IR
CDCl3) d 7.94 (d, 1H, J=8.6 Hz), 7.42 (d, 1H, J=8.6
Hz), 6.30 (s, 1H), 6.25 (s, 1H), 6.10 (bs, 1H), 3.49 (s,
3H), 3.25 (m, 4H), 2.71 (m, 4H), 1.90 (bs, 2H), 1.52
(m, 6H), 1.15 (d, 3H, J=6.3 Hz);EIMS m/z 301
C 18H29Cl2N3O (374.4), calcd,
C, 57.75;H, 7.81;N, 11.22;found, C, 57.88;H, 7.67;N,
11.15.
1
(KBr) 3360, 1713 cmꢂ1; H NMR (CDCl3) d 7.88 (d,
1H, J=7.6 Hz), 7.80 (m, 4H), 7.23 (d, 1H, J=7.6 Hz),
6.67 (s, 1H), 5.22 (bs, 1H), 3.88 (s, 3H), 3.65 (m, 2H),
3.33 (m, 1H), 3.15 (m, 2H), 2.22 (m, 4H), 1.65 (m, 20H),
1.17 (d, 3H, J=6.7 Hz);EIMS m/z 553 (M+);analysis
for C35H43N3O3 (553.7), calcd, C, 75.92;H, 7.83;N,
7.59;found, C, 75.97;H, 7.80;N, 7.48.
(M+);analysis for
6.4.2. N8-(4-Amino-1-methylbutyl)-2,5-diisopropyl-6-meth-
.
oxy-8-quinolinamine 2HCl (33). Yield: 79%;mp (salt)
6.3.7. 2-[4-(2-Isopropyl-5,6-dimethoxy-8-quinolylamino)-
pentyl]-1,3-isoindolinedione (29). Yield: 79%;oil;IR
104–106 ꢁC (dec);IR (KBr) 3430; 1H NMR (free base,
CDCl3) d 8.15 (d, 1H, J=8.1 Hz), 7.65 (m, 1H, J=8.1
Hz), 7.18 (s, 1H), 6.15 (bs, 1H), 3.72 (m, 1H), 3.45 (s,
3H), 3.29 (m, 4H), 2.73 (m, 4H), 1.95 (bs, 2H), 1.55 (m,
6H), 1.54 (m, 6H), 1.19 (d, 3H, J=6.7 Hz);EIMS m/z
343 (M+);analysis for C 21H35Cl2N3O (416.4), calcd, C,
60.57;H, 8.47;N, 10.09;found, C, 60.45;H, 8.33;N,
10.37.
1
(KBr) 3260, 1720 cmꢂ1; H NMR (CDCl3) d 8.10 (d,
1H, J=8.0 Hz), 7.82 (m, 4H), 7.37 (d, 1H, J=8.0 Hz),
6.84 (s, 1H), 4.81 (bs, 1H), 3.97 (s, 3H), 3.86 (s, 3H),
3.52 (m, 3H), 3.20 (m, 1H), 1.70 (m, 2H), 1.46 (m, 2H),
1.32 (m, 6H), 0.98 (d, 3H, J=6.7 Hz);ESIMS m/z 462
(M+1);analysis for C 27H31N3O4 (461.6), calcd, C,

M. Jain et al. / Bioorg. Med. Chem. 12 (2004) 1003–1010
1009
6.4.3. N8-(4-Amino-1-methylbutyl)-2-cyclopentyl-6-meth-
(418.4), calcd, C, 57.41;H, 7.95;N, 10.04;found, C,
57.33;H, 7.99;N, 10.23.
.
oxy-8-quinolinamine 2HCl (34). Yield: 62%;mp (salt)
90–92 ꢁC (dec);IR (KBr) 3294, 2953 cm ꢂ1; H NMR
1
(free base, CDCl3) d 7.97 (d, 1H, J=8.2 Hz), 7.45 (d,
1H, J=8.2 Hz), 6.32 (s, 1H), 6.29 (s, 1H), 6.08 (bs, 1H),
3.89 (s, 3H), 3.71 (m, 1H) 3.48 (m, 2H) 3.12 (m, 1H),
2.64 (m, 4H), 1.93 (bs, 2H), 1.75 (m, 8H), 1.11 (d, 3H,
6.4.9. N8-(4-Amino-1-methylbutyl)-2-cyclohexyl-5,6-di-
.
methoxy-8-quinolinamine 2HCl (40). Yield: 67%;mp
ꢁ
(salt) 117–119 C (dec);IR (KBr) 3310 cm ꢂ1; H NMR
(free base, CDCl3) d 8.21 (d, 1H, J=9.1 Hz), 7.49 (d,
1H, J=9.1 Hz), 6.41 (s, 1H), 6.03 (bs, 1H), 3.97 (s, 3H),
3.86 (s, 3H), 3.62 (m, 1H), 2.78 (t, 2H), 1.91 (bs, 2H),
1.78 (m, 5H), 1.42 (m, 10H), 1.31 (d, 3H, J=6.9 Hz);
EIMS m/z 368 (M+);analysis for C 22H35Cl2N3O2
(444.4), calcd, C, 59.45;H, 7.94;N, 9.45;found, C,
59.64;H, 8.24;N, 9.17.
1
J=6.9 Hz);EIMS
m/z 327 (M+);analysis for
C20H31Cl2N3O (400.4), calcd, C, 60.00;H, 7.80;N,
10.49;found, C, 60.12;H, 7.72;N, 10.45.
6.4.4. N8-(4-Amino-1-methylbutyl)-2,5-dicyclopentyl-6-
.
methoxy-8-quinolinamine 2HCl (35). Yield: 75%;mp
(salt) 110–112 ꢁC (dec);IR (KBr) 3300, 2955 cm ꢂ1; H
1
NMR (free base, CDCl3) d 7.98 (d, 1H, J=8.1 Hz), 7.22
(d, 1H, J=8.1 Hz), 6.61 (s, 1H), 6.10 (bs, 1H), 3.89 (s,
3H), 3.71 (m, 1H) 3.45 (m, 2H) 3.15 (m, 2H), 2.65 (m,
4H), 1.91 (bs, 2H), 1.79 (m, 16H), 1.20 (d, 3H, J=6.4
Hz);EIMS m/z 395 (M+);analysis for C 25H39Cl2N3O
(468.5), calcd, C, 64.09;H, 8.39;N, 8.97;found, C,
63.87;H, 8.44;N, 8.77.
6.5. General method for the synthesis of N8-(4-amino-1-
methylbutyl)-2-tert-butyl-6-methoxy-8-quinolinamine-Z-
amino acid conjugates (41–44)
To an ice cooled stirred solution of N8-(4-amino-
1-methylbutyl)-2-tert-butyl-6-methoxy-8-quinolinamine
(2, 1 mmol) and Z-l-amino acid (1.1 mmol) in CH2Cl2
(15 mL), DCC (1.1 mmol) was added. Reaction mixture
was allowed to attain room temperature and stirring
was continued for another 4 h. The reaction mixture
was kept in refrigerator overnight and the separated 1,3-
dicyclohexylurea (DCU) was filtered. Filtrate was
washed with saturated sodium bicarbonate solution
(3ꢀ5 mL) followed by water (2ꢀ5 mL), and dried over
Na2SO4. The solvent was removed under reduced
pressure to afford the crude product, which was purified
by flash column chromatography on silica gel (230–
400 mesh) using CH3OH:CHCl3 (2:98) to afford the N8-
(4-amino-1-methylbutyl)-2-tert-butyl-6-methoxy-8-qui-
nolinamine-Z-amino acid conjugates (41–44) as viscous
oil.
6.4.5. N8-(4-Amino-1-methylbutyl)-2-cyclohexyl-6-meth-
.
oxy-8-quinolinamine 2HCl (36). Yield: 59%;mp (salt)
101–104 ꢁC (dec);IR (KBr) 3417 cm ꢂ1; H NMR (free
1
base, CDCl3) d 7.92 (d, 1H, J=8.4 Hz), 7.44 (d, 1H,
J=8.4 Hz), 6.36 (s, 1H), 6.28 (s, 1H), 6.05 (bs, 1H), 3.91
(s, 3H), 3.73 (m, 1H) 3.48 (m, 2H) 3.12 (m, 1H), 2.64 (m,
4H), 1.88 (bs, 2H), 1.75 (m, 10H), 1.11 (d, 3H, J=6.5
Hz);EIMS m/z 341 (M+);analysis for C 21H33Cl2N3O
(414.4), calcd, C, 60.86;H, 8.03;N, 10.14;found, C,
60.66;H, 8.15;N, 10.33.
6.4.6. N8-(4-Amino-1-methylbutyl)-2,5-dicyclohexyl-6-
.
methoxy-8-quinolinamine 2HCl (37). Yield: 75%;mp
(salt) 88-90 ꢁC (dec);IR (KBr) 3400 cm ꢂ1; H NMR
1
(free base, CDCl3) d 7.93 (d, 1H, J=7.8 Hz), 7.28 (d,
1H, J=7.8 Hz), 6.75 (s, 1H), 6.15 (bs, 1H), 3.95 (s, 3H),
3.71 (m, 1H) 3.42 (m, 2H) 3.05 (m, 2H), 2.62 (m, 4H),
1.97 (bs, 2H), 1.78 (m, 20H), 1.15 (d, 3H, J=6.7 Hz);
EIMS m/z 423 (M+);analysis for C 27H43Cl2N3O
(496.4), calcd, C, 65.31;H, 8.73;N, 8.46;found, C,
65.45;H, 8.32;N, 8.44.
6.5.1. {1-[4-(2-tert-Butyl-6-methoxy-quinolin-8-ylamino)-
pentylcarbamoyl]-ethyl}-carbamic acid benzyl ester (41).
1
Yield: 93%;oil;IR (KBr) 3293, 1647 cm ꢂ1; H NMR
(CDCl3) d 7.88 (d, 1H, J=8.5 Hz), 7.44 (d, 1H, J=8.5
Hz), 7.33 (m, 5H), 6.32 (s, 1H), 6.27 (s, 1H), 5.88 (bs,
1H), 5.34 (bs, 1H), 5.08 (s, 2H), 3.87 (m, 4H), 3.59 (m,
1H), 3.30 (m, 2H), 1.66 (m, 2H), 1.42 (s, 9H), 1.31 (d,
3H, J=6.7 Hz), 0.91 (m, 6H);ESIMS m/z 521 (M+1);
analysis for C30H40N4O4 (520.7), calcd, C, 69.20;H,
7.74;N, 10.76;found, C, 69.34;H, 7.85;N, 10.79.
6.4.7. N8-(4-Amino-1-methylbutyl)-2-isopropyl-5,6-di-
.
methoxy-8-quinolinamine 2HCl (38). Yield: 95%;mp
(salt) 112–114 ꢁC (dec);IR (KBr) 3330, 2900 cm ꢂ1; H
1
NMR (free base, CDCl3) d 8.18 (d, 1H, J=7.8 Hz), 7.35
(d, 1H, J=7.8 Hz), 6.87 (s, 1H), 6.03 (bs, 1H), 3.95 (s,
3H), 3.82 (s, 3H), 3.55 (m, 4H), 1.97 (bs, 2H), 1.70 (m,
2H), 1.46 (m, 2H), 1.32 (m, 6H), 0.98 (d, 3H, J=6.8
6.5.2. {1-[4-(2-tert-Butyl-6-methoxy-quinolin-8-ylamino)-
pentylcarbamoyl]-2-methyl-propyl}-carbamic acid benzyl
ester (42). Yield: 92%;oil;IR (KBr) 3394, 1712, 1655
cmꢂ1; 1H NMR (CDCl3) d 7.87 (d, 1H, J=8.5 Hz), 7.43
(d, 1H, J=8.5 Hz), 7.22 (m, 5H), 6.31 (s, 1H), 6.25 (s,
1H), 6.20 (bs, 1H), 5.18 (s, 2H), 5.04 (bs, 1H), 4.13 (m,
2H), 3.87 (s, 3H), 3.60 (m, 2H), 3.30 (m, 4H), 1.68 (m,
4H), 1.42 (s, 9H), 1.31 (d, 3H, J=6.7 Hz), 1.12 (m, 6H);
ESIMS m/z 549 (M+1);analysis for C 29H46N4O4
(548.7), calcd, C, 70.04;H, 8.08;N, 10.21;found, C,
70.17;H, 8.36;N, 10.37.
Hz);ESIMS
m/z 331 (M+1);analysis for
C19H31Cl2N3O2 (404.4), calcd, C, 56.43;H, 7.73;N,
10.37;found, C, 56.47;H, 7.59;N, 10.07.
6.4.8. N8-(4-Amino-1-methylbutyl)-2-tert-butyl-5,6-di-
.
methoxy-8-quinolinamine 2HCl (39). Yield: 96%;mꢂp1
(salt) 122–125–102 ꢁC (dec);IR (KBr) 3388, 2958 cm
;
1H NMR (free base, CDCl3) d 8.23 (d, 1H, J=9.0 Hz),
7.48 (d, 1H, J=9.0 Hz), 6.40 (s, 1H), 6.03 (bs, 1H), 3.97
(s, 3H), 3.86 (s, 3H), 3.62 (m, 1H), 2.78 (t, 2H), 2.01 (bs,
2H), 1.78 (m, 4H), 1.42 (s, 9H), 1.33 (d, 3H, J=6.7 Hz);
EIMS m/z 345 (M+);analysis for C 20H33Cl2N3O2
6.5.3. {4-Benzyloxycarbonylamino-1-[4(2-tert-butyl-6-
methoxy-quinolin-8-ylamino)-pentyl-carbamoyl]-butyl}-
carbamic acid benzyl ester (43). Yield: 98%;oil;IR
1
(KBr) 3430, 1714, 1666 cmꢂ1; H NMR (CDCl3) d 7.85

1010
M. Jain et al. / Bioorg. Med. Chem. 12 (2004) 1003–1010
(d, 1H, J=8.6 Hz), 7.42 (d, 1H, J=8.6 Hz), 7.34 (m,
10H), 6.44 (bs, 1H), 6.29 (s, 1H), 6.24 (s, 1H), 6.12 (bs,
1H), 5.56 (bs, 1H), 5.08 (m, 4H), 4.36 (m, 1H), 4.23 (m,
1H), 3.88 (s, 3H), 3.72 (m, 4H), 3.56 (m, 1H), 3.21 (m,
4H), 1.55 (m, 4H), 1.42 (s, 9H), 1.26 (d, 3H, J=6.5 Hz);
APCIMS m/z 698 (M+1);analysis for C 40H51N5O6
(697.9), calcd, C, 68.84;H, 7.37;N, 10.04;found, C,
68.88;H, 7.22;N, 9.85.
6.6.3. N1-[4-(2-tert-Butyl-6-methoxy-8-quinolylamino)-
.
pentyl]-(2S)-2,5-diaminopentamide 3HCl (47). Yieꢂld1:
ꢁ
99%;mp (salt) 100–101 C (dec.);IR (KBr) 3018 cm
;
1H NMR (free base, CDCl3) d 7.85 (d, 1H, J=7.9 Hz),
7.42 (d, 1H, J=7.9 Hz), 6.30 (s, 1H), 6.23 (s, 1H), 3.85
(s, 3H), 3.58 (m, 1H), 3.44 (m, 1H), 3.25 (m, 4H), 2.95 (m,
4H), 1.91 (m, 10H), 1.40 (s, 9H), 1.26 (d, 3H, J=6.6 Hz);
ESIMS m/z 429 (M+1);analysis for C 24H42Cl3N5O2
(539.0), calcd, C, 53.48;H, 7.85;N, 12.99;found, C,
53.35;H, 7.97;N, 12.78.
6.5.4. {5-Benzyloxycarbonylamino-1-[4-(2-tert-butyl-6-
methoxy-quinolin-8-ylamino)-pentyl-carbamoyl]-pentyl}-
carbamic acid benzyl ester (44). Yield: 91%;oil;IR
6.6.4. N1-[4-(2-tert-Butyl-6-methoxy-8-quinolylamino)-
1
(KBr) 3304, 1719, 1690 cmꢂ1; H NMR (CDCl3) d 7.86
pentyl]-(2S)-2-6-diaminohexanamide 3HCl (48). Yield:
.
(d, 1H, J=8.6 Hz), 7.43 (d, 1H, J=8.6 Hz), 7.31 (m,
10H), 6.31 (s, 1H), 6.25 (s, 1H), 6.15 (bs, 1H), 5.50 (bs,
1H), 5.07 (s, 4H), 4.82 (bs, 1H), 4.13 (m, 1H), 3.85 (s,
3H), 3.58 (m, 2H), 3.27 (m, 2H), 3.12 (m, 2H), 1.67 (m,
10H), 1.41 (s, 9H), 1.25 (d, 3H, J=6.8 Hz);ESIMS m/z
712 (M+1);analysis for C 41H53N5O6 (711.9), calcd, C,
69.17;H, 7.50;N, 9.84;found, C, 69.34;H, 7.44;N,
9.94.
98%;mp (salt) 107–109 ꢁC (dec.);IR (KBr) 3435, 1667
cmꢂ1; 1H NMR (free base, CDCl3) d 7.85 (d, 1H, J=8.5
Hz), 7.42 (d, 1H, J=8.5 Hz), 6.29 (s, 1H), 6.24 (s, 1H),
5.64 (bs, 4H), 3.89 (s, 3H), 3.68 (m, 1H), 3.24 (m, 4H),
2.87 (m, 1H), 1.88 (m, 8H), 1.63 (m, 4H), 1.41 (s, 9H),
1.24 (d, 3H, J=6.7 Hz);ESIMS m/z 444 (M+1);ana-
lysis for C25H44Cl3N5O2 (553.0), calcd, C, 54.30;H,
8.02;N, 12.66;found, C, 54.68;H, 8.11;N, 12.47.
6.6. General method for the synthesis of N8-(4-amino-1-
methylbutyl)-2-tert-butyl-6-methoxy-8-quinolinamine-
amino acid conjugates (45–48)
Acknowledgements
Generous financial support from the Council of Scien-
tific and Industrial Research (CSIR), New Delhi, India
[Grant no. 01(1555)/98/EMR-II] for the synthesis of
primaquine derivatives is gratefully acknowledged.
To a mixture of Z-amino acid linked 2-tert-butylprima-
quine derivatives (41–44, 1 mmol), glacial acetic acid (1
mL) and 10% Pd-C (200 mg) in methanol (30 mL) was
bubbled a slow stream of hydrogen gas for 1 h. The
catalyst was removed by filtration, and filtrate was con-
centrated in vacuum to afford the product as oil, which
upon treatment with a solution of ethereal hydrogen
chloride provided the amino acid conjugates as hydro-
chloride salt.8
References and notes
1. (a) Frederich, M.;Donge , J.-M.;Angenot, L.;De Mol, P.
´ ´ ´
Curr. Med. Chem. 2002, 9, 1435. (b) Boss, C.;Richard-
Bildstein, S.;Weller, T.;Fischli, W.;Meyers, S.;Binkert,
C. Curr. Med. Chem. 2003, 10, 883.
6.6.1. N1-[4-(2-tert-Butyl-6-methoxy-8-quinolylamino)-
.
pentyl]-(2S)-2-aminopropanamide 2HCl (45). Yield:
2. Carson, P. E. In Antimalarial Drugs II;Peters, W.;
Richards, W. H. G. (Ed.). Springer-Verlag: New York,
1984;p 83.
3. Jain, M.;Vangapandu, S.;Sachdeva, S.;Singh, S.;Singh,
P. P.;Jena, G. B.;Tikoo, K.;Ramarao, P.;Kaul, C. L.;
Jain, R. J. Med. Chem. 2004, 47, 285.
98%;mp (salt) 89–91 ꢁC (dec.);IR (KBr) 3018, 1710
cmꢂ1; 1H NMR (free base, CDCl3) d 7.86 (d, 1H, J=7.8
Hz), 7.65 (s, 1H, J=7.8 Hz), 7.15 (s, 1H), 6.81 (s, 1H),
6.20 (bs, 1H), 5.48 (bs, 1H), 4.30 (bs, 2H), 3.99 (m, 1H),
3.87 (s, 3H), 3.71 (m, 1H), 3.26 (m, 2H), 1.84
(m, 4H), 1.50 (s, 9H), 1.25 (m, 6H);ESIMS m/z 387
(M+1);analysis for C 22H36Cl2N4O2 (459.5), calcd, C,
57.51;H, 7.90;N, 12.19;found, C, 57.58;H, 7.68;N,
12.02.
4. Baker, J. K.;Clark, A. M.;McChesney, J. D. J. Pharm.
Res. 1984, 73, 502.
5. (a) Vangapandu, S.;Sachdeva, S.;Jain, M.;Singh, S.;
Singh, P. P.;Kaul, C. L.;Jain, R. Bioorg. Med. Chem.
2004, 12, 239. (b) Jain, R.;Jain, S.;Gupta, R. C.;Anand,
N.;Dutta, G. P.;Puri, S. K. Indian J. Chem. 1994, 33B, 251.
6. Vangapandu, S.;Sachdeva, S.;Jain, M.;Singh, S.;Singh,
P. P.;Kaul, C. L.;Jain, R. Bioorg. Med. Chem. 2003, 11,
4557.
7. Jain, R.;Vangapandu, S.;Jain, M.;Kaur, N.;Singh, S.;
Singh, P. P. Bioorg. Med. Chem. Lett. 2002, 12, 1701.
8. The resolution studies on primaquine (Carroll, F. I.;Ber-
rang, B. Linn, C. P. J. Med. Chem. 1978, 21, 326) indicate
that both enantiomers possess similar antimalarial activ-
ities, and primaquine is used clinically as racemate. Thus,
in this study, attempts were not made to separate (R, S)
and (S, S) diastereoisomers of synthesized 8-quinolina-
mine conjugates (45–48).
6.6.2. N1-[4-(2-tert-Butyl-6-methoxy-8-quinolylamino)-
pentyl]-(2S)-2-amino-3-methyl-butan-amide 2HCl (46).
Yield: 94%;mp (salt) 97–99 ꢁC (dec.);IR (KBr) 3243,
1
1663 cmꢂ1; H NMR (free base, CDCl3) d 7.86 (d, 1H,
J=8.5 Hz), 7.61 (bs, 1H), 7.43 (d, 1H, J=8.5 Hz), 6.31
(s, 1H), 6.26 (s, 1H), 4.80 (bs, 1H), 4.30 (bs, 2H), 3.87 (s,
3H), 3.62 (m, 1H) 3.35 (m, 2H), 2.72 (m, 2H), 1.68 (m,
4H), 1.41 (s, 9H), 1.29 (d, 3H, J=6.5 Hz), 0.945 (m,
6H);ESIMS m/z 414 (M+1);analysis for C 24H40Cl2N4O2
(487.5), calcd, C, 59.13;H, 8.27;N, 11.49;found, C,
59.27;H, 8.39;N, 11.67.