Synthesis, photophysical properties, tumor uptake, and preliminary in vivo photosensitizing efficacy of a homologous series of 3-(1′-alkyloxy)-ethyl-3-devinylpurpurin-18-N-alkylimides with variable lipophilicity

Article abstract of DOI:10.1021/jm0005510

Starting from methylpheophorbide-a, a homologous series of purpurinimides containing alkyl substituents at two different positions [as 3-(1¹-O-alkyl) and 13²-N-alkyl] were synthesized. These compounds with variable lipophilicity (log P 5.32-16.44) exhibit long wavelength absorption near) λ_max700 nm (ε: 45 000 in dichloromethane) with singlet oxygen (¹O₂) production in the range of 57-60%. The shifts in in vivo absorptions and tumor/skin uptake of these compounds were determined in C₃H mice bearing RIF tumors by in vivo reflectance spectroscopy. The results obtained from a set of photosensitizers with similar lipophilicity (log P 10.68-10.88) indicate that besides the overall lipophilicity, the presence and position of the alkyl groups (O-alkyl vs N-alkyl) in a molecule play an important role in tumor uptake, tumor selectivity, and in vivo PDT efficacy. At present, all purpurinimide analogues are being evaluated at various doses, and experiments are underway to establish a quantitative structure-activity relationship on a limited set of compounds. The 1D and 2D NMR and mass spectrometry analyses confirmed the structures of the desired purpurinimides and the byproducts formed during various reaction conditions. The mechanisms of the formation of the unexpected 12-formyl- and 12-(hydroxymethyl)purpurinimides under certain reaction conditions are also discussed.

Full text of DOI:10.1021/jm0005510

1
540
J . Med. Chem. 2001, 44, 1540-1559
Syn th esis, P h otop h ysica l P r op er ties, Tu m or Up ta k e, a n d P r elim in a r y in Vivo
P h otosen sitizin g Effica cy of a Hom ologou s Ser ies of 3-(1′-Alk yloxy)eth yl-
3
-d evin ylp u r p u r in -18-N-a lk ylim id es w ith Va r ia ble Lip op h ilicity†
‡
‡
‡
‡
§
‡
Gang Zheng, William R. Potter, Susan H. Camacho, J oseph R. Missert, Guosheng Wang, David A. Bellnier,
‡
§
‡
,‡,|
Barbara W. Henderson, Michael A. J . Rodgers, Thomas J . Dougherty, and Ravindra K. Pandey*
Photodynamic Therapy Center, Department of Nuclear Medicine/ Radiology, Roswell Park Cancer Institute,
Buffalo, New York 14263, Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403
Received December 27, 2000
Starting from methylpheophorbide-a, a homologous series of purpurinimides containing alkyl
1
2
substituents at two different positions [as 3-(1 -O-alkyl) and 13 -N-alkyl] were synthesized.
These compounds with variable lipophilicity (log P 5.32-16.44) exhibit long wavelength
1
absorption near λmax700 nm (ꢀ: 45 000 in dichloromethane) with singlet oxygen ( O
2
) production
in the range of 57-60%. The shifts in in vivo absorptions and tumor/skin uptake of these
compounds were determined in C H mice bearing RIF tumors by in vivo reflectance spectros-
copy. The results obtained from a set of photosensitizers with similar lipophilicity (log P 10.68-
0.88) indicate that besides the overall lipophilicity, the presence and position of the alkyl
3
1
groups (O-alkyl vs N-alkyl) in a molecule play an important role in tumor uptake, tumor selec-
tivity, and in vivo PDT efficacy. At present, all purpurinimide analogues are being evaluated
at various doses, and experiments are underway to establish a quantitative structure-activity
relationship on a limited set of compounds. The 1D and 2D NMR and mass spectrometry anal-
yses confirmed the structures of the desired purpurinimides and the byproducts formed during
various reaction conditions. The mechanisms of the formation of the unexpected 12-formyl-
and 12-(hydroxymethyl)purpurinimides under certain reaction conditions are also discussed.
In tr od u ction
Photodynamic therapy (PDT) is a promising cancer
treatment that involves the combination of visible light
photosensitizers related to chlorins, bacteriochlorins,
porphycenes, phthalocyanines, naphthalocyanines, and
expanded porphyrins have been synthesized and evalu-
1
4
and a photosensitizer. Each factor is harmless by itself,
ated for PDT efficacy. However, only a few studies
but when combined with oxygen they can produce lethal
cytotoxic agents that inactivate the tumor cells. This
address the structure-activity relationships in a par-
2
4
ticular series of photosensitizer.
enables greater selectivity toward diseased tissue, as
only those cells that are simultaneously exposed to the
photosensitizer, light, and oxygen are exposed to the
cytotoxic effect. The dual selectivity of PDT is produced
by both a preferential uptake of the photosensitizer by
the diseased tissue and the ability to confine activation
of the photosensitizer to this diseased tissue by restrict-
ing the illumination to that specific region.
From our earlier work with various chlorin- and
bacteriochlorin-based compounds it has been shown that
the presence and position of the substituents in the
parent molecule make a remarkable difference in bio-
5
logical activity. Recently, in a congeneric series of the
alkyl ether derivatives of pyropheophorbide-a6 it was
observed that the in vivo photodynamic efficacy in-
creased by increasing the length of the carbon chain,
being maximum in compounds with n-hexyl and n-
heptyl chains at position-3 (ring A). The structural
elements evaluated in this in vivo quantitative struc-
ture-activity relationship (QSAR) study included the
length and shape (alkyl, alkenyl, cyclic, and secondary
Photofrin, a hematoporphyrin derivative, is the only
photosensitizer that has been approved worldwide for
3
the treatment of various types of cancers by PDT. It
fits some of the criteria for ideal photosensitizers, but
it suffers from several drawbacks. First, it is a complex
mixture of various monomeric, dimeric, and oligomeric
forms. Second, its long wavelength absorption falls at
7
analogues) of the ether side chain. Thus, three end
points, including tumor growth delay, tumor cell lethal-
ity, and vascular perfusion, revealed highly similar
QSAR patterns that constituted a function of the alkyl
ether chain length and drug lipophilicity, which is
defined as the log of the n-octanol:water partition
coefficient (log P). When compensated for differences in
tumor photosensitizer concentration, the n-hexyl de-
rivative (HPPH) (optimal lipophilicity) was 5-fold more
potent than the n-dodecyl derivative (more lipophilic)
and 3-fold more potent than the n-pentyl analogues (less
lipophilic). Therefore, drug lipophilicity was highly
predictive for photodynamic activity. To determine the
effect of the alkyl ether side chains in other series of
6
30 nm, which lies well below the wavelength necessary
for the maximum tissue penetration. Finally, it induces
prolonged cutaneous phototoxicity, a major adverse
effect associated with most of the porphyrin-based
photosensitizers. Therefore, in recent years a variety of
†
A part of this work was presented at the first International
Conference on Porphyrins and Phthalocyanines (ICPP-1), Dijon,
France, J une 2000.
*
Corresponding author. Phone: (716) 845-3203. Fax: (716) 845-
8
920. E-mail: ravindra.pandey@roswellpark.org.
‡
Photodynamic Therapy Center, Roswell Park Cancer Institute.
Bowling Green State University.
Department of Nuclear Medicine/Radiology, Roswell Park Cancer
§
|
Institute.
1
0.1021/jm0005510 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/03/2001

3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1541
8
photosensitizers, Pandey et al. introduced a series of
O-alkyl side chains at position-8 (ring B) of the most
effective isomer of benzoporphyrin derivative (ring A
reduced BPD). Among these analogues, the related 8-(1′-
hexyloxyethyl)-8-devinyl analogue was found to be more
effective than BPD.8
for the alkyl ether analogues of the pyropheophorbide
series, we decided to extend this approach to photosen-
sitizers with longer wavelength absorption. For our
1
2
study, purpurin-18 1a
was selected as a starting
material due to (a) its ready availability from chloro-
phyll a; (b) its strong absorption at ∼700 nm, which has
an advantage over other porphyrin-based photosensi-
tizers in treating deeply seated tumors; and (c) its high
singlet oxygen yield, as well as inherent photosensitiz-
ing ability demonstrated by in vitro studies. Purpurin-
In the present study we wanted to explore the effect
of the presence of such substituents on photosensitizers
different from pyropheophorbide and BPD in their pho-
tophysical, physicochemical, and steric factors and to
examine the generality of the structure-activity relation-
ship we had previously established for the alkyl ether
analogues of pyropheophorbide-a. We believe that infor-
mation obtained from these studies coupled with those
previously obtained from other series of compounds will
be of immense value in developing an improved photo-
sensitizer with required photophysical properties.
1
8 also provides an opportunity for modifying the
functional groups substituted at the peripheral positions
such as the vinyl, fused anhydride ring, and propionic
acid side chain. These modifications generate a series
of photosensitizers with variable lipophilicity, thus
avoiding many different multistep total syntheses.
Ch em ica l Tr a n sfor m a tion of th e Exocyclic An -
1
3
Im p or ta n ce of th e Lip op h ilicity. In medicinal
chemistry, lipophilicity has proven to be an important
molecular descriptor that often is well-correlated with
the bioactivity of drugs. Lipophilicity is indicated by
lipophilic indices, such as the logarithm of a partition
coefficient, log P, which reflects the equilibrium parti-
tioning of a molecule between a nonpolar and a polar
h yd r id e Rin g. Smith et al. have shown that purpu-
rin-18 in the presence of an alkylamine forms the
related imide derivatives in a low yield if the reaction
mixture is left at room temperature for several weeks.
We were interested in evaluating this class of com-
pounds as it presents a unique opportunity to alter the
lipophilicity of the molecule by substituting various
N-alkyl groups at the fused imide ring and also by
replacing the 3-vinyl group with a series of O-alkyl
derivatives. Therefore, our first objective was to develop
an efficient general method for the preparation of
purpurin-18-N-alkylimides, which could then be modi-
fied into a series of desired analogues.
9
phase, such as an n-octanol/water system. Partition
coefficients can be measured experimentally by several
techniques, ranging from the simple “shake flask”
technique to quite popular chromatographic methods
such as HPLC. For designing new compounds in a
particular series, it is necessary to develop efficient
methods for altering the lipophilicity by introducing a
variety of substituents or by modifying the basic skel-
eton. Hence, numerous theoretical methods have been
developed to predict lipophilicity based on the log P
value. The most frequently applied methods are based
on the fragmental approach,10 making use of the addi-
tive-constitutive nature of log P. The basic idea of these
methods lies in the definition of π, the substituent
constant, π ) log PX - log PY, where PX is the partition
coefficient of a derivative and PY is that of the parent
compound. It is found that, although π values vary for
a given functional group depending on its electronic
environment, such variation is small.11 For example, the
π value for a methyl (CH3) group is 0.5, which is mostly
true for both aromatic and aliphatic systems. Adding
one saturated carbon group will increase the log P value
by 0.5. Thus, the easiest way to alter the lipophilicity
of a parent molecule is to introduce alkyl chains with
variable carbon units.
For our study, methylpheophorbide-a 1, isolated from
1
4
Spirulina pacifica, was converted into purpurin-18
1
2
methyl ester 2 and was used as a substrate. As shown
in Scheme 1, reaction of 2 (λmax 699 nm) with various
alkylamines (e.g. n-hexylamine) at room temperature
gave the corresponding amides in high yield (95%), as
a mixture of 3e and 4e in the ratio of 6:1. The amide 4e
was obtained as a minor product, because of the steric
hindrance caused by the adjacent reduced pyrrole ring
during the ring-opening reaction, and was assigned as
2
15 -amide, whereas the major product 3e was assigned
2
as the 3 -amide by NMR spectroscopy. Attempts to
convert amides 3e and 4e into the corresponding imides
9e by following the methods used in other aromatic
systems mainly produced the decomposition products.
Leaving the amide solution in CH2Cl2 or THF at room
temperature for 1 week gave a mixture of purpurins
with cyclic anhydride 2 (699 nm) and cyclic imide 9e
(705 nm) in minor amounts and the starting material
In the pyropheophorbide series it has been observed
that the log of the HPLC retention time is linearly
related to the carbon chain length for the corresponding
alkyl ether derivative. Similarly, calculated log P values
as a major product. Refluxing the reaction mixture at
elevated temperatures slightly improved the yield of
purpurin anhydride without formation of any desired
imide analogue. Various attempts were then made to
optimize the reaction conditions, and these are sum-
marized in Table 1. Interestingly, reaction of the
mixture of amides 3e and 4e in the presence of Mont-
morillonite K-10 clay and CH2Cl2 as a solvent gave a
mixture of cyclic imide 9e as a minor product (12%) and
anhydride analogue 1 as the major component (85%),
which could be separated by column chromatography.
(pH 7.4), predicted by a computer program module of
the PALLAS system, were linear with chain length,
7
ranging from 3.1 for C1 to 8.6 for C12. Measured log P
values were also in agreement with the calculated
values. Thus, for a congeneric series of compounds, it
is possible to determine their log P values with the
PALLAS computer program and by HPLC experiments
and to confirm these results by the classical “shake
flask” method.
To avoid the formation of the undesirable cyclic
anhydride 1, it was thought to be necessary to activate
the carboxylic function of intermediate amides, which
could generate the desired imide analogue via intramo-
Str u ctu r e Mod ifica tion of Ch lor op h yll a sth e
Str a tegic Con sid er a tion . Having developed a QSAR

1
542 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Zheng et al.
Sch em e 1
Ta ble 1. Percentage Yields of Purpurinimide and Isoimide
under Various Reaction Conditionsa
starting
method
no.
amide anhydride imide isoimide
conditions
THF, ∆, 4 h
(%)
(%)
(%)
(%)
1
2
25
70
5
0
imidazole, 140 °C,
decomposition
1
h
3
K-10 clay, CH
4 h
Cl
DCC
DCC; K-10 clay, RT
DCC; DBU, RT
DCC; DBU, ∆, 2 h
DCC; KOH/MeOH
RT, 5 min
2
Cl
2
,
0
80-85
10-12
0
2
4
5
6
7
8
9
CH
2
2
, 10 days
50
0
100
100
40
0
20-25
15-20
0
0
0
60
85
0
95
0
0
0
0
0
0
0
0
0
1
1
1
1
0
1
2
3
DCC; pTS, CH
TCD
2
Cl
2
95
nd
100
0
0
0
0
50
0
0
0
10
0
0
0
0
TCD; DBU, RT
TCD; DBU, toluene,
, 2 h
∆
1
1
4
5
TCD; DBU, THF, ∆
TCD; KOH/MeOH,
RT, 10 min
60
90
0
0
30
10
0
0
1
F igu r e 1. Partial NMR spectra of purpurin-18-13 -N-hexyl-
1
isoimide (7e) and purpurin-18-15 -hexylisoimide (8e). The
reduced ring D caused a significant upfield shift in the
1
6
CH
2
N
2
; KOH/MeOH,
0
0
85
0
RT, 5 min
resonances of the 17H proton in 8e (R ) hexyl).
a
1
DCC, dicyclohexylcarbodiimide; TCD, 1,1 -thiocarbonyldiimid-
azole; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; nd, not deter-
mined.
yield. This isomeric mixture was found to be a mixture
of purpurin isoimide 7e and 8e by NMR (proton and
C-13) and high-resolution mass spectroscopic studies.
Separation of this mixture gave isomerically pure pur-
purinimides 7e and 8e with long wavelength absorp-
tions at λmax 696 and 690 nm, respectively. The structure
lecular cyclization. Thus, two pathways were investi-
gated. In the first approach, reaction of purpurin amides
3
e and 4e with dicyclohexylcarbodiimide (DCC) afforded
1
a mixture of two isomers in a ratio of 6:1, in 96% overall
of the minor product 7e was further confirmed as 15 -

3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1543
Sch em e 2
Sch em e 3. A Possible Mechanism for the Formation of
a Fused Isoimide Ring System
isoimide on the basis of the observation of NOE interac-
tions between the 15 -N-alkyl group and the 17 -methyl
2
3
1
(
(
CO2Me) group. Surprisingly, in their H NMR spectra
1
Figure 1), 17H resonance of the 15 -isoimide 8e ap-
1
peared downfield compared to that of 13 -isoimide 7e,
presumably due to an electronic resonance effect in-
duced by the N-alkyl group. Such unique 1H NMR
characteristics can thus be employed for distinguishing
2
2
the 13 and 15 -isoimides. Treatment of isoimides 7e
and 8e individually or together as an isomeric mixture
with DBU/toluene at 60 °C produced imide 9e in 60%
yield. Interestingly, replacing DBU with stronger bases,
such as methanolic KOH at room temperature, gave the
desired purpurin-18-N-hexylimide 9e in 85% yield.
In the second approach, the intermediate amide
mixture containing 3e and 4e was converted into
corresponding methyl esters 5a and 6a by reacting with
diazomethane, followed by brief methanolic KOH treat-
ment to produce the desired imide analogue 9e in
excellent yield (>80%, Scheme 2). Because of the dif-
ficulty of removing dicyclohexylurea as an impurity in
our first approach, this methodology was found to be
more suitable for preparing various purpurin-18-N-
alkylated imides.
Scheme 3 outlines two possible mechanisms for the
formation of N-alkyl isoimide (e.g. 7e) by the dehydra-
tion of the intermediate amide (e.g. 3e) with DCC, as
well as its final conversion into the corresponding imide
six-member-ring formation has also been proposed in
1
5
other aromatic systems. Further base treatment cleaves
the isoimide ring of 7e, and the resulting intermediate
amide under intramolecular cyclization could afford the
desired imide 9e. In both approaches, during the forma-
tion of imide analogue, several byproducts, 12, 13, 14,
and 16, were also isolated (Schemes 3-5). Among these
analogues, chlorin 14, a slightly slower moving com-
pound than 8e in TLC exhibited similar visible absorp-
tion spectrum as the parent imide 7. In their NMR
spectrum, compound 14 has an extra broad signal
(compared to 8e) at 6.9 ppm integrated for one proton
9
e. Thus, donation of a proton from the amide 3e to
DCC could lead to intermediate 13, which could decom-
pose via the indicated quasi-six-member-ring transition
state 14 into N-substituted cyclic isoimides 7e. It can
also be postulated that reaction of DCC with amide 5
first generates the unstable DCC derivative 15, which
upon intramolecular cyclization would produce another
unstable isoimide and eventually afford the desired
isoimide 7e and dicyclohexylurea as a byproduct. Such

1
544 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Zheng et al.
F igu r e 3. The interactions shown by various protons in
purpurinimide 9e. The assignments are based on the results
obtained from the 2D ROESY NMR studies.
N-hexylimide 13. As shown in Figure 2, the presence of
a sharp singlet at 6.1 ppm, integrating for two protons,
and the absence of the 12-methyl resonances confirmed
the proposed structure. The structure of compound 13
was further confirmed by mass spectrometry analysis
F igu r e 2. Partial NMR spectra: (A) 12-methylpurpurin-18-
n-hexylimide 9e; (B) the unstable intermediate 16; (C) the 12-
hydroxymethyl derivative 13; and (D) the related 12-formyl
analogue 12.
(m/z ) 692.2) and 2D-ROESY NMR studies.
There are two possible mechanisms for the formation
of the 12-formyl analogue 12. First, in the presence of
light, the compound possibly undergoes a [4 + 2] cyclo-
addition reaction with singlet oxygen. As shown in
Scheme 4, the photooxidation of purpurin-18-imide 9e
under aqueous basic conditions on exposure to light will
produce the corresponding 12-formyl derivative 12. To
3
(
Figure 1). The 17 -methyl (CO2Me) observed at 3.6 ppm
for parent imide 9e was found to be absent. Further-
more, mass spectrometry analysis also confirmed the
proposed structure (m/z ) 731.4 for R ) hexyl). On the
basis of these observations, the structure of 14 was
3
1
assigned as 17 -hexylamide purpurin-18-N-hexylimide,
confirm the involvement of O2, the reaction was per-
apparently formed by the condensation of the methyl
ester functionality with unreacted 1-hexylamine.
The other byproduct (a minor component) observed
just behind purpurinimide 9e as a green band in
preparative thin-layer chromatography was isolated in
formed in the dark (under a nitrogen atmosphere) and,
as expected, no formyl analogue was isolated. The
second mechanism (in the absence of light) is postulated
on the basis of the isolation of the 12-hydroxymethyl
derivative 13 obtained as a minor compound. As shown
in Scheme 5, deprotonation of amide 9e will lead to its
enolization form, which on reacting with the molecular
oxygen will form an intermediate, which on cleavage of
the O-O bond will afford the intermediate anion. This
could follow two pathways: If the reaction sequences
follow pathway A, the intermediate, under intramolecu-
lar base-catalyzed cyclization, would yield the lactone
16 (for NMR see Figure 2) and that will eventually pro-
duce 12-(hydroxymethyl)purpurin-18-N-alkylimide 13.
If it follows pathway B, the intermediate could under-
go further enolization, which on reacting with molecular
oxygen will generate the 12-dihydroxymethyl derivative.
The dehydration of the unstable dihydroxymethyl de-
rivative will produce 12-formylpurpurin-18-N-alkyl-
imide 12. A more straightforward path from interme-
diate “A” to aldehyde 12 could also involve heterolytic
cleavage of the protonated peroxide with loss of H2O.
1
0% yield. The electronic absorption spectrum of the
byproduct exhibited a long wavelength absorption at 717
nm, and compared with the parent imide 9e it had a
1
bathchromic shift of 12 nm. The H NMR spectrum of
the product (Figure 2) showed an extra singlet (one
proton) at 11.9 ppm along with the meso-protons’
resonances; which appeared at 10.3, 8.9, and 8.2 ppm
for 10H, 5H and 20H, respectively. The 12-methyl signal
observed at 3.8 ppm for the parent imide 9e was
missing, and the mass spectrometry analysis gave a
molecular ion peak at m/z of 690.2 (R ) heptyl), which
was 18 amu more than the corresponding imide (m/z )
6
72.4, R ) heptyl). On the basis of these results, the
structure of the byproduct was assigned as 12-formylpur-
purin-18-N-heptylimide 12.
The third byproduct obtained as the most polar band
was characterized as 12-(hydroxymethyl)purpurin-18-

3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1545
Sch em e 4. A Possible Mechanism for the Formation of 12-Formyl Analog in Presence of Singlet Oxygen
Sch em e 5. A Possible Mechanism for the Formation of 12-Formylpurpurinimide via the Corresponding
1
2-Hydroxymethyl Analog in Presence of Molecular Oxygen
Vin yl Mod ifica tion . Another functional group in
For the preparation of 3-alkyl ether analogues of
purpurin-18-based photosensitizers, a series of purpu-
rin-18-N-alkylimides 9a -9i containing N-methyl to
N-decyl carbon units, respectively, were used as sub-
strates. Theoretically, if these compounds are individu-
ally reacted with various alkyl alacohols of 1-12 carbon
units, there is a possibility of producing 144 compounds,
having partition coefficient values ranging from 5.32 to
16.44. In Table 2, on the basis of their lipophilicity, these
compounds were divided into five groups: group I
(shown in red), log P ) 5.3-7.8; group II (shown in
purpurin-18 methyl ester 2 available for chemical
modification is the vinyl group present at positon-3 of
the macrocycle. On the basis of the previous QSAR
studies with the pyropheophorbide ethers,7 we have
shown that the overall lipophilicity of the molecule can
be influenced by introducing various alkyl ether sub-
stituents in ring A of the macrocycle. Therefore, we
decided to investigate the effect of a series of such
3
-alkoxyalkyl substituents of various purpurin-18-N-
alkylimide in PDT efficacy.

1
546 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Zheng et al.
Ta ble 2. Possible Combinations of the Alkyl Substituents (1-12 Carbon Units) at Two Different Positions of
Purpurin-18-N-alkylimides (1-12 Carbon Units) and Their Calculated log P Values***
*R1 ) alkyl ether; e.g., 1 represents methyl, 2 represents ethyl, ... 12 represents dodecyl; R2 ) alkylimide; e.g. 1 represents methyl, 2
represents ethyl, ... 12 represents dodecyl. **The desired reagents are commercially not available. ***On the basis of their lipophilicity,
compounds were divided into five groups: I (red), log P ) 5.3-7.8; II (green), log P ) 8.2-9.3; III (blue), log P ) 9.8-10.8; IV (magenta),
log P ) 11.3-12.3; V (black), log P ) 12.8-16.4.
green), log P ) 8.2-9.3; group III (shown in blue), log
P ) 9.8-10.8; group IV (shown in magenta), log P )
photosensitizers listed in Table 4 and to try to investi-
gate a correlation of photosensitizing ability with their
lipophilicity and in vivo tumor uptake.
1
1.3-12.3; group V (shown in black), log P ) 12.8-16.4.
Instead of synthesizing the whole series, we decided to
select the least numbers which could cover the entire
range of log P values and the greatest variety in
structure. Table 4 summarizes the list of purpurin-
imides synthesized with substituents at two different
positions with their calculated log P values. Compounds
shaded with red color have R1 ) R2 ) 1-12 (methyl to
dodecyl); compounds shaded with blue color have the
same lipophilicity (R1 + R2 ) 13 ) 11 methylene units
A general method for the preparation of the desired
alkyl ether analogues of purpurinimides 9a -9i and the
formation of byproducts under certain reaction condi-
tions is depicted in Schemes 1 and 2. In a typical
procedure, purpurin-18-N-hexylimide 9e was reacted
with 30% HBr/acetic acid and the residue obtained after
removing the acid, and then reaction with 1-heptanol
produced the desired 3-(1-heptyloxy)ethylpurpurin-18-
N-hexylimide 37 (60% yield) as a major component and
3-(1-heptyloxy-2-bromo)ethyl derivative 15 as a minor
product (Scheme 2). The bromo derivative 15 moves
extremely close to its parent compound in TLC and was
separated only after repeated preparative thin-layer
chromatography. The structures of the starting materi-
als (e.g., see Figure 3) and the final products were
+
2 methyl terminal groups); compounds shaded with
2
green color have fixed length of 13 -alkylimide side
chain (R2 ) hexyl); and compounds shaded with yellow
color have fixed length of 3-(1-alkyl ether) side chain
(R1 ) hexyl). Table 4 represents a classic example in
which compounds 37, 42, and 45 have the alkyl ether
and N-alkyl substituents at various positions with
similar log P values (10.73-10.88) and similar photo-
physical characteristics. The singlet oxygen yields,
measured in benzene, were similar for all the purpu-
rinimides and were 0.70 ( 0.05. Therefore, our aim was
to investigate the PDT efficacy of these and the related
1
confirmed by H NMR and mass spectroscopy. Com-
1
pared to compound 37, in which 3 -proton resonance
appears as a quartet at ∼5.7 ppm due to the adjacent
1
methyl coupling, the 3 -proton of the bromo derivative
15 shows a triplet at ∼5.8 ppm caused by the adjacent
2
2
3 -bromomethyl. In compound 37, 3 -methyl appears as

3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1547
F igu r e 4. An example of maintaining the similar lipophilicity of various imide analogues by introducing various alkyl substituents
at different positions of the molecule.
F igu r e 5. Absorption and fluorescence spectra of purpurin-
imide 37 (in dichloromethane) excitation of the absorption peak
at 699 nm produced emission at 705 nm.
F igu r e 6. HPLC retention times of a series of 3-(1′-alkoxy)
ethyl analogues with variable carbon units of purpurin-18-N-
hexylimide showing a linear correlation with the lipophilicity
of the molecule.
a doublet at upfield region ∼2 ppm, whereas in com-
pound 15, this signal is replaced with a doublet of
doublets at ∼4.2 ppm. The formation of this product
could be eliminated by maintaining anhydrous condi-
tions, using fresh HBr/AcOH (avoiding Br2), and adding
anhydrous K2CO3 as an acid quencher before reacting
with the desired alcohol. The alkyl ether analogues
exhibited strong absorption (ꢀ ) 45 000) at near 700 nm.
The absorption and fluorescence spectra of a represen-
tative compound are shown in Figure 5.
linear relationship with log P and HPLC retention time.
The log P values at pH 7.4 (calculated by the Prolog D
module of PALLAS software, Compudrug Chemistry,
Ltd. Budapest) showed a linear relationship with the
chain length, ranging from 7.82 (33) to 13.38 (41) with
C-1 to C-12 carbon units. Similar correlation was also
observed between the retention times and the log P
values. Therefore, the calculated log P values presented
for various analogues in Table 4 represent the actual
lipophilicity of this series of compounds.
Rela tion sh ip betw een Molecu la r Str u ctu r e a n d
Lip op h ilicity. As shown in Figure 6, the alkyl ether
analogues of purpurin-18-N-hexylimides exhibited a

1
548 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Zheng et al.
in vivo reflectance spectroscopy.17 In brief, the experi-
ment measures the light scattered by the tissue. For
these experiments, the mice were first anesthetized
using ketamine xylazine intraperitoneally. The optical
power as a function of wavelength was recorded before
the iv injection of the photosensitizer. The drug was
then injected and the spectrum again recorded. The in
vivo drug absorption spectrum is best displayed by
taking the ratio of the postinjection spectrum to the
preinjection spectrum. This ratio offers the same ad-
vantages as a double-beam absorption spectrophotom-
eter. The preinjection mouse data can be thought of as
the reference beam sample (typically a cuvette and
solvents), and the postinjection data as the sample beam
containing everything in the reference beam plus the
experimental drug.
Ta ble 3
singlet oxygen
quantum yield
singlet oxygen
quantum yield
compd no.
compd no.
2
3
0
3
0.59
0.57
41
42
0.57
0.60
Sin glet Oxygen Qu a n tu m Yield s. Purpurinimides
0, 33, 41, and 42 with variable lipophilicity were
2
subjected to the assay for quantum yield of singlet
oxygen. Benzene was used as solvent throughout. The
solutions were continuously stirred with a stream of
oxygen. All experiments were carried out at room
temperature. As can be seen from Table 3, the difference
in overall lipophilicity of the molecules did not produce
any significant difference in singlet oxygen yields and
were observed in the range of 57-60%.
Deter m in a tion of Tu m or Up ta k e by in Vivo
Reflecta n ce Sp ectr oscop y. Most of the purpurinim-
ides were insoluble in water and for the biological
studies were dissolved in a 1% Tween 80/5% dextrose
solution. The concentration of the photosensitizers in
the solutions was calculated on the basis of their ex-
tinction coefficient values, using the Beer-Lambert
law.16
For measuring the tumor uptake, the purpurinimides
were injected into mice at a dose of 5.0 µmol/kg. Most
of the purpurinimides produced high tumor uptake, and
some of them showed considerable difference in tumor
to skin uptake at 24 h postinjection, indicating enhanced
tissue selectivity, an advantage for all photosensitizers
in achieving high therapeutic ratio. These data indicate
that, in the purpurinimide series, altering the length
of the N-alkyl- or O-alkyl ether carbon chains resulted
in a significant change in tumor uptake. In a series of
We have previously shown that the absorption spec-
trum of a compound in living tissue can be obtained by
Ta ble 4. A List of Alkyl Ether Analogs of Purpurin-18-N-alkylimide Synthesized and Their Calculated log P Values
*
R1 ) alkyl ether; e.g. 1 represents methyl, 2 represents ethyl, ... 12 represents dodecyl. R2 ) alkylimide; e.g., 1 represents methyl, 2
represents ethyl, ... 12 represents dodecyl. **The desired reagents were not available.

3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1549
pounds, e.g. 29, 42, 43, 44, and 45, with same number
of total carbon units (O-alkyl + N-alkyl; R1 + R 2 ) 13)]
and log P values ranging from 10.68 to 10.88 were
evaluated at a lower drug dose (0.4 µmol/kg). As can be
seen from Figure 7, among these analogues, purpurin-
imide 43 (R1 ) decyl, R2 ) propyl) was most effective
and produced 67% tumor response on day 30. However,
two out of six mice died immediately after the light
treatment. The surviving four mice were without
tumor regrowth on day 30. It was interesting to observe
that the related isomer 44 (R1 ) propyl, R2 ) decyl)
showed only 30% tumor response on day 20, with
complete tumor regrowth on day 25. Photosensitizer 45
(R1 ) methyl, R2 ) dodecyl) showed 100% tumor
regrowth on day 20. However, its related isomer 42 (R1
F igu r e 7. In vivo photosensitizing efficacy of certain purpu-
rinimides with the same number of total carbon units (O-alkyl
+
N-alkyl ) 13) and similar log P values. The mice (six mice/
)
dodecyl, R2 ) methyl) was found to be more effective
group) were treated with light at 702 nm (in vivo absorption)
and produced 35% tumor response on day 30. Under
similar treatment conditions, purpurinimide 29 (R1 )
hexyl, R2 ) heptyl) produced 30% tumor response on
day 30.
at 24 h postinjection. Drug dose: 0.4 µM/kg. Compound 29
(
O-hexyl + N-heptyl ) 13 carbon units), 42 (O-dodecyl +
N-methyl ) 13 carbon units), 43 (O-decyl + N-propyl ) 13
carbon units), 44 (O-propyl + N-decyl ) 13 carbon units), 45
(O-methyl + N-dodecyl ) 13 carbon units). Note: In case of
Attempts were also made to determine a correlation
between in vivo photosensitizing efficacy of these ana-
logues with tumor uptake obtained by in vivo reflectance
spectroscopy at an injected dose of 5.0 µmol/kg, a
nontoxic dose in the absence of light treatment. As
shown in Table 5, tumor uptake ranged from 4.77 to
photosensitizer 29, two of six mice died immediately after the
light treatment. Thus, on the basis of the surviving mice, 100%
tumor response was observed on day 30.
1
1.5 µmol/kg, except for 16, which was extremely low
at 0.3 µmol/kg. For compounds with a similar lipophi-
licity, an interesting observation was noted. For ex-
ample, compound 45 (R1 ) methyl, R2 ) dodecyl, log P
)
10.88) produced higher drug uptake in tumor (15.48
µmol/kg) than 42 (R1 ) dodecyl, R2 ) methyl, log P )
0.73, uptake 6.21µmol/kg), but exhibited better tumor
1
selectivity (tumor-to-skin ratio) 3.57). Similar patterns
were observed in other photosensitizers with similar log
P values, even with significant difference in tumor
uptake. For example photosensitizers 25 (log P ) 7.67)
and 33 (log P ) 7.82) showed 6.42 and 10.10 µmol/kg
tumor uptake, respectively. Interestingly, 32 and 41
with the same lipophilicity (log P ) 13.38) produced 2.00
and 4.30 µmol/kg tumor uptake, respectively. Thus,
among the purpurinimides studied so far, in a group of
compounds with similar lipophilicity a significant dif-
ferences in their in vivo tumor uptake and tumor-to-
skin ratios were observed. This could be due to a
significant difference in their pharmacokinetic and
pharmacodynamic characteristics, the subject of ongoing
studies.
F igu r e 8. In vivo tumor vs skin uptake of various alkyl ether
analogues of N-alkyl purpurinimides in C
with RIF tumors determined by in vivo reflectance spectros-
copy at a dose of 5.0 µmol/kg. R and R are O-alkyl and N-alkyl
substituents with variable carbon units respectively (numbers
3
H mice implanted
1
2
1
, 2, 4-12 indicate the number of carbon units present in
In summary, in this paper we have described the
synthesis and tumor and skin uptake of a series of long-
wavelength photosensitiizers related to purpurinimides
with variable lipophilicity. The photophysical data
indicate that this class of compounds has high singlet
oxygen producing ability, a key cytotoxic agent for PDT
which is not significantly affected by varying the lipo-
philicity. The preliminary in vivo results are quite
encouraging and suggest their great potential as effec-
tive photosensitizers for photodynamic therapy. How-
ever, for QSAR studies, it is of utmost importance to
evaluate the photosensitizing efficacy of these com-
pounds at various nontoxic doses. Detailed pharmaco-
kinetic and pharmacodynamic studies are required to
establish QSAR, and these experiments are currently
in progress.
O-alkyl and N-alkyl side chains).
compounds with variable lipophilicity, the skin vs tumor
uptake are summarized in Figure 8.
P r elim in a r y in Vivo Stu d ies. To relate the molec-
ular structure of the photosensitizers to their in vivo
therapeutic response, the photosensitizing efficacy of
photosensitizers was evaluated in C3H mice implanted
7
with RIF tumors. In initial experiment, groups of six
mice were treated at a dose of 1.0 µmol/kg and a light
dose of 135 J /cm2 at 702 nm (in vivo absorption).
However, this drug dose was proved to be toxic to many
of the animals following the light treatment. To deter-
mine the effect(s) of the presence and position of the
O-alkyl and N-alkyl carbon chains, a group of com-

1
550 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Zheng et al.
Ta ble 5. Tumor and Skin Uptake in C3H Mice Implanted with RIF Tumors of Various Purpurinimidea
tumor
skin
tumor
skin
compd
no.
uptake uptake tumor/skin
compd
no.
uptake uptake tumor/skin
R1 and R2
log P
(µmol)
(µmol)
ratio
2.87
R1 and R2
log P
(µmol)
(µmol)
ratio
3.15
1
1
2
3
2
3
2
4
4
2
6
8
5
3
7
4
0
3
2
9
R1 ) methyl
R2 ) methyl
R1 ) propyl
R2 ) propyl
R1 ) hexyl
R2 ) methyl
R1 ) methyl
R2 ) hexyl
R1 ) hexyl
R2 ) propyl
R1 ) propyl
R2 ) hexyl
R1 ) hexyl
R2 ) hexyl
R1 ) decyl
R2 ) propyl
5.32
0.30
0.10
37
44
45
39
31
32
41
23
24
R1 ) heptyl
R2 ) hexyl
R1 ) propyl
R2 ) decyl
R1 ) methyl
R2 ) dodecyl
10.83
8.20
2.60
7.26
7.67
10.5
6.42
10.10
4.95
13.8
7.30
10.26
6.21
8.04
4.8
2.19
3.61
2.24
3.34
2.19
3.17
2.40
3.57
2.73
10.83
10.88
11.50
15.48
10.70
5.18
6.09
5.80
3.54
1.80
2.00
4.30
1.73
2.70
1.89
2.67
3.02
2.88
2.39
2.19
3.21
1.87
1.78
4.5
7.82
R1 ) nonanyl 11.85
R2 ) hexyl
8.79
1.48
6.29
2.30
4.28
1.74
2.95
R1 ) hexyl
R2 ) decyl
R1 ) hexyl
R2 ) dodecyl
R1 ) dodecyl
R2 ) hexyl
R1 ) decyl
R2 ) decyl
R1 ) dodecyl
R2 ) dodecyl
12.36
13.38
13.38
14.40
16.44
8.79
4.77
10.32
10.68
9.40
5.56
R1 ) dodecyl 10.73
R2 ) methyl
R1 ) hexyl
R2 ) heptyl
5.04
10.83
a
The in vivo uptake was determined by in vivo reflectance spectroscopy at a dose of 5.0 µmol/kg.
2
2
Exp er im en ta l Section
trans-3 CHdCH
(
2
); 6.20 (d, J ) 11.7,1H, cis-3 CHdCH
2
); 5.20
m, J ) 9.4, 2.5 Hz, 1H for 17H); 4.46 (q, J ) 7.1 Hz, 1H for
Gen er a l Met h od s. Melting points (uncorrected) were
measured on a hot-stage apparatus. UV-vis spectra were
1
1
3
7
8H); 3.77 (s, 3H, 12CH
3
); 3.63 (q, J ) 7.9 Hz, 2H, 8 CH
); 3.32 and 3.15 (each s, 3H, 2CH and
); 2.66, 2.45, 2.34, and 1.99 (each m, 1H, 2 × 17 H and 2
2
2
);
2
.59 (s, 3H, 17 CO
CH
2
CH
3
3
recorded on a Varian (Cary-50 Bio) spectrophotometer. 1
H
1
3
NMR spectra were recorded in CDCl
3
using a Brucker 400
×
17 H); 1.73 (d, J ) 7.6 Hz, 3H, 18CH
3
); 1.65 (t, J ) 7.6 Hz,
MHz instrument. Mass spectrometry analyses were performed
at the Department of Molecular and Cellular Biophysics, RPCI,
Buffalo, NY, and at the University of Michigan, East Lansing,
MI. Elemental analysis was obtained from Midwest Microlab,
LLC, Indianapolis, IN. Where necessary, solvents were dried
before use.
2
3
H, 8 CH
3
); 0.25 and -0.12 (each br s, 1H, 2NH). HRMS calcd
C
34
H
34
N
4
O
5
: 578.2524. Found: 579.2634 (M + 1).
Gen er a l P r oced u r e for th e P r ep a r a tion of P u r p u r in -
8-N-a lk ylim id es. In a typical experiment, purpurin-18
methyl ester (500 mg) dissolved in CH Cl was treated with
large excess of various alkylamines (0.5 mL) at room temper-
ature for 24 h. The disappearance of the 699 nm band and
the appearance of a new 666 nm band in the UV-vis spectrum
indicated the completion of the reaction. The reaction solvent
and the excess of amine were then evaporated under high
vacuum (at or below 30 °C) to give a residue. After crystal-
1
2
2
P u r p u r in -18 Meth yl Ester (2). Methyl pheophorbide a 1
(2 g) was dissolved in 800 mL of diethyl ether. A KOH solution
in 1-propanol (24 g dissolved in 80 mL) and 30 mL of pyridine
were then added. Air was then bubbled into the solution for 1
h. The reaction mixture was extracted with water (500 mL).
The aqueous layer was collected and its pH was adjusted to
lization from CH
2 2
Cl /hexanes, an isomeric mixture of chlorin-
2
-4 with cold H
CH Cl /THF (3:1 ratio, 400 mL). Evaporation of the solvent
gave a purple residue. This residue was crystallized from CH
Cl /n-hexanes and washed with water until neutral. It was
2
SO
4
solution (25%). It was then extracted with
p -N-alkylamides 3 and 4 (520 mg) so obtained was used for
the next step without further purification.
Meth od 1. The amide intermediates 3 and 4 (500 mg)
2 2
dissolved in 50 mL of CH Cl was treated with DCC (700 mg)
6
2
2
2
-
2
then air-dried overnight to a purple powder, and the crude
purpurin-18 carboxylic acid was obtained in 50% (900 mg)
yield. Then, 500 mg of this product was reacted with diazo-
methane, generated by an Aldrich mini-Diazald apparatus, to
produce purpurin-18 methyl ester. The residue was chromato-
at room temperature for 24 h. The reaction was monitored
spectrophotometrically. In the UV-vis spectrum, appearance
of a new peak at 696 nm marked the completion of the
reaction. After the workup (diluted with CH Cl , washed with
2 2
water and brine solution, dried over anhydrous sodium sulfate,
and filtered and the solvent evaporated), the residue was
redissolved in the minimum amount of CH Cl and kept in a
2 2
freezer for 1 h to precipitate out the dicyclohexyl urea as a
white solid. The solution obtained after filtration was evapo-
graphed on a silica column with acetone/CH
the title compound was obtained in 80% yield (410 mg) after
crystallizing from CH Cl /n-hexane as purple red crystals. Mp:
67 °C. UV-vis λmax (in CH
2 2
Cl (2% v/v), and
2
2
5
2
(
6
2
Cl
2
): 410 nm (ꢀ 1.23 × 10 ), 478
3
3
4
3
5.1 × 10 ), 508 (7.5 × 10 ), 546 (2.46 × 10 ), 642 (9.8 × 10 ),
rated. The crude product was chromatographed on a silica
4
1
1
99 (4.95 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
, δ
column, eluted with 3% acetone in CH
2
Cl
2
. Purpurin-18-13 -
ppm): 9.60, 9.39, 8.58 (each s, 1H, for 5H, 10H and 20H); 7.90
(N-alkyl)isoimide methyl ester 7 (λmax ) 696 nm, moving slow
1
1
(
dd, J ) 18.1, 11.7 Hz, 1H, 3 CHdCH
2
); 6.30 (d, J ) 18.1,1H,
in column) and purpurin-18-15 -(N-alkyl)isoimide methyl ester

3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
(λmax ) 690 nm, moving fast in column) were isolated as
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1551
for 5H); 8.58 (s, 1H, for 20H); 7.88 (dd, J ) 18.0, 11.4 Hz, 1H,
8
individual isomers in 60% and 20% yield, respectively. For the
preparation of imide analogue, the mixture of 7 and 8 was then
treated with methanolic KOH at room temperature for 3-5
min. The reaction mixture was diluted with 200 mL of CH
Cl
solution of acetic acid (2% v/v), 2 × 400 mL water. The organic
layer was then dried over anhydrous sodium sulfate, filtered,
and evaporated to afford a residue. This residue was chro-
matographed on a silica column eluting with 2% acetone/CH
Cl
to gave the desired purpurinimides 7 in ∼80% yield.
Meth od 2. Amide intermediates 3 and 4 were dissolved in
CH Cl and treated with diazomethane; the methyl ester
3CHdCH
11.4,1H, 3CHdCH
CH ); 4.39 (q, J ) 7.3 Hz, 1H for 18H); 3.81 (s, 3H, 12CH
3.61 (q, J ) 7.8 Hz, 2H, 8 CH
(s, 3H, 2CH ); 3.13 (s, 3H, 7CH
2
); 6.28 (d, J ) 18.0,1H, 3CHdCH
2
); 6.13 (d, J )
2
); 5.39 (m, 1H for 17H); 4.56 (m, 2H, N-CH -
2
3
3
);
); 3.35
3
); 2.72, 2.41 and 2.00 (each m,
1
2
2
-
2 2 3
); 3.57 (s, 3H, 17 CO CH
2
, and washed immediately with 2 × 400 mL aqueous
3
1
2
1H + 2H + 1H, 2 × 17 H and 2 × 17 H); 1.76 (d, J ) 7.0 Hz,
2
3H, 18CH
Hz, 3H, N-CH
Mass calcd for C36
3
); 1.65 (t, J ) 7.0 Hz, 3H, 8 CH
3
); 1.59 (t, J ) 6.3
2
CH
3
); -0.11 and -0.20 (each br s, 1H, 2NH).
: 605.3. Found: 606.8 (M + 1).
2
-
H
39 5 4
N O
2
P u r p u r in -18-N-p r op ylim id e (9c). Purpurin-18 methyl
ester 2 (410 mg) was reacted with 1-propylamine (1.0 mL) by
following method 2, and the corresponding imide was isolated
in 88% yield (385 mg). Mp: 212-214 °C.UV-vis (in CH Cl ):
2
2
derivatives 5 and 6 so obtained were then reacted with
methanolic KOH for 5 min. The reaction was monitored by
UV-vis spectrophotometry.
2
2
4
4
4
705 (4.5 × 10 ), 647 (1.2 × 10 ), 549 (2.3 × 10 ), 510 (1.0 ×
4
3
5
1
10 ), 483 (8 × 10 ), 417 (1.2 × 10 ). H NMR (400 MHz, 3 mg/1
mL CDCl , δ ppm): 9.63 (s, 1H, for 10H); 9.38 (s, 1H, for 5H);
8.58 (s, 1H, for 20H); 7.91 (dd, J ) 18.0, 11.7 Hz, 1H, 3CHd
CH
Following the standard workup, the desired purpurinimide
3
9
was obtained in ∼80% yield.
2
); 6.29 (d, J ) 18.0,1H, 3CHdCH
CHdCH ); 5.40 (m, 1H for 17H); 4.43 (m, 2H, N-CH
); 4.34 (q, J ) 7.3 Hz, 1H for 18H); 3.84 (s, 3H, 12CH
2
); 6.16 (d, J ) 11.7,1H,
2
CH -
Isom er ic Mixtu r e of Ch lor in -p
6
-15-ca r boxylic Acid 13-
-13-
3
2
2
Hep tyla m id e 17-P r op ion ic Ester (3f) a n d Ch lor in -p
6
CH
3
3
);
.66 (q, J ) 7.8 Hz, 2H, 8 CH ); 3.36
3
s, 3H, 2CH ); 3.18 (s, 3H, 7CH ); 2.68 and 2.40 (each m, 1H
ca r boxylic Acid 15-Hep tyla m id e 17-P r op ion ic Ester (4f):
Purpurin-18-methyl ester 2 (500 mg) was reacted with n-
heptylamine (1 mL) and converted into the related amide
1
2
3
(
+
2 2 3
); 3.56 (s, 3H, 17 CO CH
3
1
2
2
2H for 2 × 17 H and 1 × 17 H); 2.02 (m, 3H, 1 × 17 H and
derivative, which after crystallization from CH
2 2
Cl /n-hexanes
N-CH
2
CH CH ); 1.76 (d, J ) 7.0 Hz, 3H, 18CH ); 1.67 (t, J )
2
3
3
produced the title compound in 95% yield (565 mg). UV-vis
2
4
7.0 Hz, 3H, 8 CH ); 1.19 (t, J ) 6.3 Hz, 3H, N-CH CH CH );
in a solution of THF/CH
2
Cl
10 ), 528 (1.73 × 10 ), 498 (4.92 × 10 ), 402 (5.11 × 10 ) H
NMR of the mixture of 3f and 4f in a ratio of 3:1 (400 MHz, 3
mg/1 mL CDCl , δ ppm): 9.70, 9.62 and 8.82 (each s, 1H, for
H, 10H, and 20H of 4f); 9.69, 9.61, and 8.76 (each s, 1H, for
H, 10H, and 20H of 3f); 8.08 (dd, J ) 17.4, 11.4 Hz, 1H, 3CHd
2
(1:4): 666 (1.78 × 10 ), 612 (1.85
3
2
2
3
3
3
3
4
1
-0.08 and -0.17 (each br s, 1H, 2NH). HRMS calcd for
×
C
37
H
41
N
H
5
O
4
: 620.3237 (M + 1). Found: 620.3221. Anal. Calcd
1
for C37
41
N
5
O
4
2 2
‚ / H O: C, 70.66; H, 6.73; N, 11.14. Found: C,
3
7
0.90; H, 6.67; N, 11.03.
5
5
P u r p u r in -18-N-bu tylim id e (9d ). Purpurin-18 methyl es-
ter 2 (200 mg) was reacted with 1-butylamine (1.0 mL) by
following method 2, and the corresponding imide was isolated
1
CH
.07 (br s, 1H, 13 NHCH
d, J ) 17.4,1H, 3CHdCH
2
); 7.12 (br s, 1H, 15 NHCH
2
CH
CH CH
); 6.14 (d, J ) 11.9, 1H, 3CHdCH
2
CH
2
CH
2
2
CH
2
CH
2
CH
of 3f); 6.34
);
3
of 4f);
1
7
(
5
3
2
CH
2
2
2
CH
CH
2
CH
3
4
2
2
in 75% yield (164 mg). UV-vis (in CH
2
Cl
2
): 705 (4.5 × 10 ),
4
4
4
3
.05 (m, 1H for 17H); 4.37 (m, 1H for 18H); 3.85, 3.78 and
647 (1.2 × 10 ), 549 (2.3 × 10 ), 510 (1.0 × 10 ), 483 (8 × 10 ),
5 1
3
1
.70 (m, 4H, NHCH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
and 8 CH
2
2
of 3f
417 (1.2 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
ppm): 9.59 (s, 1H, for 10H); 9.35 (s, 1H, for 5H); 8.58 (s, 1H,
for 20H); 7.89 (dd, J ) 18.0, 11.7 Hz, 1H, 3CHdCH ); 6.28 (d,
J ) 18.0,1H, 3CHdCH ); 6.14 (d, J ) 11.7,1H, 3CHdCH );
5.41 (m, 1H for 17H); 4.47 (m, 2H, N-CH CH CH CH ); 4.36
(q, J ) 7.3 Hz, 1H for 18H); 3.82 (s, 3H, 12CH ); 3.63 (q, J )
); 3.35 (s, 3H,
); 2.69 and 2.40 (each m, 1H + 2H for
, δ
and 4f); 3.59 (s, 3H, 12CH
3
2
of 3f and 4f); 3.49 (s, 3H, 17 CO
2
-
CH
and 7CH
CH CH
1
0
3
of 4f); 3.47 (s, 3H, 17 CO
2
CH
3
of 3f); ∼3.31 (s, 6H, 2CH
3
2
3
of 3f and 4f); 2.50 (m, 2H, NHCH
2
CH CH CH CH
2
2
2
2
-
2
2
2
3
); 2.37, 2.14 and 1.99 (each m, 1H + 2H + 1H, 2 ×
2
2
2
3
1
2
2
7 H and 2 × 17 H); 1.73 (m, 6H, 18CH
3
and 8 CH
); -1.62 and -1.90
: 693.4.
3
); 1.50-
3
1
2
.42 (m, N-CH CH CH CH CH CH CH
2
2
2
2
2
2
3
7.8 Hz, 2H, 8 CH
2CH ); 3.15 (s, 3H, 7CH
2 × 17 H and 1 × 17 H); 1.99 (m, 3H, 1 × 17 H and
N-CH CH CH CH ); 1.76 (d, J ) 7.0 Hz, 3H, 18CH ); 1.66 (t,
J ) 7.0 Hz, 3H, 8 CH ); 1.27 (m, 2H, N-CH CH CH CH ); 1.10
(t, J ) 6.3 Hz, 3H, N-CH CH CH CH ); -0.10 and -0.19
(each br s, 1H, 2NH). Mass calcd for C38 633.3.
O: C,
2 2 3
); 3.56 (s, 3H, 17 CO CH
(
each br s, 1H, 2N-H). Mass calcd for C41
H
51
N
5
O
5
3
3
1
2
2
Found: 693.4 (M + 1).
P u r p u r in -18-N-m eth ylim id e (9a ). Reaction of purpurin-
8-methyl ester 2 (200 mg) with methylamine (1.5 mL, 2.0 M
2
2
2
3
3
2
1
3
2
2
2
3
solution in THF) generated the related amide derivative. After
treatment with diazomethane, the intermediate on reacting
with methanolic KOH produced the title compound in 70%
yield (142 mg) after purification (Alumina grade III column
2
2
2
3
43 5 4
H N O :
1
Found: 634.5 (M + 1). Anal. Calcd for C38
H
43
N
5
O
4
2 2
‚ / H
72.00; H, 6.84; N, 11.05. Found: C, 72.10; H, 6.90; N, 10.70.
with dichloromethane). Mp: 209-211 °C. UV-vis (in CH
2
-
P u r p u r in -18-N-h exylim id e (9e). Purpurin-18 methyl es-
ter 2 (500 mg) was reacted with 1-hexylamine (1.0 mL) by
following method 2, and the corresponding imide was isolated
in 80% yield (455 mg). Mp: 221-223 °C. UV-vis (in CH Cl ):
4
4
4
Cl
2
): 705 (4.5 × 10 ), 647 (1.2 × 10 ), 549 (2.3 × 10 ), 510 (1.0
4 3 5 1
×
10 ), 483 (8 × 10 ), 417 (1.2 × 10 ). H NMR (400 MHz, 3
mg/1 mL CDCl
3
, δ ppm): 9.54 (s, 1H, for 10H); 9.31 (s, 1H, for
2
2
4
4
4
5
3
1
H); 8.57 (s, 1H, for 20H); 7.87 (dd, J ) 18.0, 11.4 Hz, 1H,
CHdCH ); 6.28 (d, J ) 18.0,1H, 3CHdCH ); 6.13 (d, J )
1.4,1H, 3CHdCH ); 5.35 (m, 1H for 17H); 4.36 (q, J ) 7.3
); 3.78 (s, 3H, N-CH );
); 3.34
); 2.72, 2.43, and 2.00 (each
705 (4.5 × 10 ), 647 (1.2 × 10 ), 549 (2.3 × 10 ), 510 (1.0 ×
4 3 5 1
2
2
10 ), 483 (8 × 10 ), 417 (1.2 × 10 ). H NMR (400 MHz, 3 mg/1
2
mL CDCl , δ ppm): 9.64 (s, 1H, for 10H); 9.39 (s, 1H, for 5H);
3
Hz, 1H for 18H); 3.85 (s, 3H, 12CH
3
3
3
8.58 (s, 1H, for 20H); 7.84 (dd, J ) 17.4, 11.2 Hz, 1H, 3CHd
CH ); 6.27 (d, J ) 17.4,1H, 3CHdCH ); 6.16 (d, J ) 11.2,1H,
1
2
.59 (q, J ) 7.8 Hz, 2H, 8 CH
2 2 3
); 3.59 (s, 3H, 17 CO CH
2
2
(s, 3H, 2CH ); 3.12 (s, 3H, 7CH
3
3
2 2 2 2 2
3CHdCH ); 5.40 (m, 17H); 4.46 (m, 2H, N-CH CH CH CH -
1
2
m, 1H + 2H + 1H, 2 × 17 H and 2 × 17 H); 1.75 (d, J ) 7.0
CH CH ); 4.31 (q, J ) 7.3 Hz, 1H for 18H); 3.84 (s, 3H, 12CH );
2
3
3
2
1
2
Hz, 3H, 18CH
3
); 1.64 (t, J ) 7.0 Hz, 3H, 8 CH
3
); -0.08 and
2 2 3
3.67 (q, 2H, 8 CH ); 3.57 (s, 3H, 17 CO CH ); 3.31 (s, 3H,
-
0.16 (each br s, 1H, 2NH).
Mass calcd for C35
P u r p u r in -18-N-eth ylim id e 9b. Reaction of purpurin-18
2CH ); 3.11 (s, 3H, 7CH ); 2.68 and 2.39 (each m, 1H + 2H, 2
3
1
3
2
2
H
37
N
5
O
4
: 591.3. Found: 592.9 (M + 1).
× 17 H and 1 × 17 H); 1.99 (m, 3H, 1 × 17 H and N-CH
2
CH
); 1.64 (t, J
2
-
CH
7.2 Hz, 3H, 8 CH
CH CH CH CH CH
2
CH
2
CH
2
CH
3
); 1.74 (d, J ) 7.2 Hz, 3H, 18CH
3
2
)
3
2
); 1.61-1.31 (m, total for 6H, N-CH -
methyl ester 2 (200 mg) with ethylamine (1.5 mL, 2.0 M
solution in THF) produced the related amide derivative. The
intermediate after treatment with diazomethane was reacted
with methanolic KOH, which afforded the title compound in
2
2
2
2
3
); 0.95 (t, 3H, N-CH
2
CH
2
CH
2
2 2 3
CH CH CH );
-
N
0.07 and -0.16 (each br s, 1H, 2NH). Mass calcd for C40H -
47
1
5
O
4
: 661.4. Found: 661.3. Anal. Calcd for C40
H
47
N
5
O
4
2 2
‚ / H O:
C, 71.60; H, 7.21; N, 10.44. Found: C, 71.64; H, 7.10; N, 10.29.
7
0% yield (146 mg) after purification (Alumina grade III
column with dichloromethane). Mp: 213-215 °C. UV-vis (in
P u r p u r in -18-N-h ep tylim id e (9f). Purpurin-18 methyl
ester 2 (500 mg) was reacted with 1-heptylamine (1.0 mL) by
following method 2, and the corresponding imide was isolated
in 75% yield (437 mg). Purpurin-18 methyl ester 2 (410 mg)
4
4
4
CH
2
Cl
2
): 705 (4.5 × 10 ), 647 (1.2 × 10 ), 549 (2.3 × 10 ), 510
4 3 5 1
(
1.0 × 10 ), 483 (8 × 10 ), 417 (1.2 × 10 ). H NMR (400 MHz,
3
3
mg/1 mL CDCl , δ ppm): 9.57 (s, 1H, for 10H); 9.33 (s, 1H,

1
552 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Zheng et al.
CH ); 1.76 (d,
was reacted with 1-heptylamine (1.0 mL) by following method
2
mg). UV-vis (in CH
N-CH
2
CH
2
CH
2
CH
2
CH
3
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
3
2
, and the corresponding imide was isolated in 75% yield (437
J ) 7.2 Hz, 3H, 18CH
); 1.67 (t, J ) 7.2 Hz, 3H, 8 CH
3
); 1.62-
4
4
2
Cl
2
): 705 (4.5 × 10 ), 647 (1.2 × 10 ), 549
1.29 (m, total for 18H, N-CH
2
CH
); 0.88 (t, 3H, N-CH
CH CH
2
CH
2
CH
2
CH
CH
2
CH
2
CH
2
CH
2
-
-
4
4
3
5
1
(
2.3 × 10 ), 510 (1.0 × 10 ), 483 (8 × 10 ), 417 (1.2 × 10 ). H
CH
2
CH
2
CH
2
CH
CH
3
2
CH
2
2
CH
2
CH
2
CH
2
NMR (400 MHz, 3 mg/1 mL CDCl
3
, δ ppm): 9.62 (s, 1H, for
0H); 9.39 (s, 1H, for 5H); 8.59 (s, 1H, for 20H); 7.84 (dd, J )
7.4, 11.2 Hz, 1H, 3CHdCH ); 6.27 (d, J ) 17.4,1H, 3CHd
); 6.16 (d, J ) 11.2, 1H, 3CHdCH ); 5.40 (m, 17H); 4.46
m, 2H, N-CH CH CH CH CH CH CH ); 4.31 (q, J ) 7.3 Hz,
H for 18H); 3.84 (s, 3H, 12CH ); 3.67 (q, 2H, 8 CH
); 3.31 (s, 3H, 2CH ); 3.11 (s, 3H, 7CH
CH
2
CH
2
CH
2
2
2
3
); -0.14 and -0.17 (each br s, 1H,
: 747.5. Found: 747.0. Anal.
2 2
‚ / H O: C, 73.16; H, 8.01; N, 9.28.
1
1
CH
(
1
3
59 5 4
2NH). Mass calcd for C46H N O
Calcd for C46
Found: C, 73.06; H, 7.99; N, 8.87.
1
2
H
59
N
5
O
4
2
2
1
2
2
2
2
2
2
3
P u r p u r in -18-13 -(N-h exyl)isoim id e Meth yl Ester (7e).
1
3
2
); 3.57 (s,
); 2.68
Purpurin-18 methyl ester 2 (500 mg) was reacted with 1-hex-
ylamine. The intermediate amide analogue on reacting with
dicyclohexylcarbodiimide (DCC) produced a mixture of the title
2
H, 17 CO
2
CH
3
3
1
3
2
and 2.39 (each m, 1H + 2H, 2 × 17 H and 1 × 17 H); 1.99 (m,
2
3
H, 1 × 17 H and N-CH
2
CH
2
CH
2
CH2-CH
2
CH2-CH
3
); 1.74 (d,
1
compound and its isomer, 15 -isoimide 8e. Chromatographic
2
J ) 7.2 Hz, 3H, 18CH
3
); 1.64 (t, J ) 7.2 Hz, 3H, 8 CH
.38 (m, total for 8H, N-CH CH CH CH CH CH CH
t, 3H, N-CH CH CH CH CH CH CH ); -0.17 and -0.46
49 5 4
each br s, 1H, 2NH). Mass calcd for C41H N O : 675.4 (M ).
3
); 1.62-
); 0.95
separation on silica column with 2-5% MeOH in dichlo-
romethane afforded 8e in 20% yield (115 mg) and 7e in 60%
yield (345 mg).UV-vis (in CH Cl , rel ꢀ): 696 (0.396), 639
1
(
(
2
2
2
2
2
2
3
2
2
2
2
2
2
3
2
2
+
(0.057), 537 (0.175), 501 (0.109), 411 (1.000). 1H NMR (400
1
Found: 676.4 (M + 1). Anal. Calcd for C41
7
H
49
N
5
O
4
‚ /
2
H
2
O: C,
MHz, 3 mg/1 mL CDCl , δ ppm): 9.74 (s, 1H, for 10H); 9.57
(s, 1H, for 5H); 8.75 (s, 1H, for 20H); 7.94 (dd, J ) 19.2, 12.5
3
1.88; H, 7.36; N, 10.23. Found: C, 72.10; H, 7.32; N, 10.15.
P u r p u r in -18-N-octylim id e (9g). Purpurin-18 methyl ester
(200 mg) was reacted with 1-octylamine (1.0 mL) by following
Hz, 1H, 3CHdCH
J ) 12.5,1H, 3CHdCH
1H for 18H); 4.06 (m, 2H, N-CH
(s, 3H, 12CH ); 3.74 (q, J ) 7.5 Hz, 2H, 8 CH
); 3.42 (s, 3H, 2CH ); 3.24 (s, 3H, 7CH
2
2
); 6.33 (d, J ) 19.2,1H, 3CHdCH ); 6.15 (d,
2
2
); 5.24 (m, 17H); 4.52 (q, J ) 7.3 Hz,
CH CH CH CH CH ); 3.81
); 3.56 (s, 3H,
); 2.65 (m,
method 2, and the corresponding imide was isolated in 75%
2
2
2
2
2
3
4
1
yield (178 mg). UV-vis (in CH
2
Cl
2
): 705 (4.5 × 10 ), 647 (1.2
3
2
4
4
4
3
2
×
10 ), 549 (2.3 × 10 ), 510 (1.0 × 10 ), 483 (8 × 10 ), 417 (1.2
17 CO
2
CH
3
1
3
3
5
1
1
2
×
10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
, δ ppm): 9.58
1H, 1 × 17 H); 2.51-2.00 (m, total for 7H, 1 × 17 H, 2 × 17 H
(
s, 1H, for 10H); 9.33 (s, 1H, for 5H); 8.58 (s, 1H, for 20H);
and N-CH
18CH
N-CH
CH CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
2
); 1.76 (d, J ) 8.0 Hz, 3H,
); ∼1.58 (m, total for 4H,
7
1
1
.89 (dd, J ) 17.4, 11.2 Hz, 1H, 3CHdCH
H, 3CHdCH ); 6.13 (d, J ) 11.2,1H, 3CHdCH
7H); 4.46 (m, 2H, N-CH CH CH CH CH CH CH
2
); 6.26 (d, J ) 17.4,
); 5.42 (m,
CH ); 4.37
); 3.60 (q, 2H,
); 3.11 (s, 3H,
3
); 1.68 (t, J ) 7.2 Hz, 3H, 8 CH
3
2
2
2
CH
CH
2
CH
CH
2
CH
CH
2
CH
2
CH
3
2
); 0.98 (t, J ) 7.8 Hz, 3H, N-CH -
2
2
2
2
2
2
2
3
2
2
2
2
3
); -0.66 and -0.84 (each br s, 1H, 2N-
(q, J ) 7.3 Hz, 1H for 18H); 3.81 (s, 3H, 12CH
3
H). HRMS calcd for C40
H
47
N
5
O
4
: 661.3621. Found: 661.3620.
1
2
1
8
7
2
CH
CH
2
); 3.57 (s, 3H, 17 CO
2
CH
3
); 3.35 (s, 3H, 2CH
3
P u r p u r in -18-15 -(N-h exyl)isoim id e Meth yl Ester (8e).
UV-vis (in CH Cl , rel ꢀ): 690 (0.565), 639 (0.082), 543 (0.193),
1
2
3
); 2.72 and 2.39 (each m, 1H, 2 × 17 H and 1 × 17 H);
2
2
2
1
.01 (m, 3H, 1 × 17 H and N-CH
2
2
CH
3
2
CH
2
CH
2
CH
2
CH
2
CH
2
-
507 (0.101), 411 (1.000). H NMR (400 MHz, 3 mg/1 mL CDCl ,
3
CH
3
); 1.74 (d, J ) 7.2 Hz, 3H, 18CH
CH ); 1.62-1.25 (m, total for 10H, N-CH
CH CH CH ); 0.90 (t, 3H, N-CH CH CH CH
); 1.64 (t, J ) 7.2 Hz, 3H,
δ ppm): 9.73 (s, 1H, for 10H); 9.49 (s, 1H, for 5H); 8.65 (s, 1H,
8
3
2
CH
CH
2
CH
2
CH
CH
2
CH
CH
2
-
);
for 20H); 7.92 (dd, J ) 17.4, 11.2 Hz, 1H, 3CHdCH ); 6.31 (d,
2
2
2
3
2
2
2
2
2
CH
2
2
3
J ) 17.4, 1H, 3CHdCH ); 6.18 (d, J ) 11.2, 1H, 3CHdCH );
2
2
-
C
C
0.14 and -0.23 (each br s, 1H, 2NH). Mass calcd for
5.26 (m, 17H); 4.57 (q, J ) 8.0 Hz, 1H for 18H); 4.01 (m, 2H,
N-CH CH CH CH CH CH ); 3.83 (s, 3H, 12CH ); 3.76 (q, J
42
H
H
51
N
N
5
O
O
4
: 690.6. Found: 690.6 (M + 1). Anal. Calcd for
2
2
2
2
2
3
3
1
1
2
42
51
5
4
‚ /
2
H
2
O: C, 73.10; H, 7.45; N, 10.15. Found: C,
) 7.5 Hz, 2H, 8 CH ); 3.58 (s, 3H, 17 CO CH ); 3.46 (s, 3H,
1
2
2
3
7
2.91; H, 7.47; N, 9.90.
2CH ); 3.28 (s, 3H, 7CH ); 2.65 (m, 1 × 17 H); 2.58-2.00 (m,
1 2
2 2 2 2
3
3
P u r p u r in -18-N-d ecylim id e (9h ). Purpurin-18 methyl es-
total for 7H, 1 × 17 H, 2 × 17 H, and N-CH
CH CH ); 1.78 (d, J ) 7.2 Hz, 3H, 18CH ); 1.72 (t, J ) 7.2 Hz,
3H, 8 CH CH CH CH CH
); ∼1.61 (m, total for 4H, N-CH
CH CH CH -
ter 2 (200 mg) was reacted with 1-heptylamine (1.0 mL) by
following method 2, and the corresponding imide was isolated
in 75% yield (185 mg). UV-vis (in CH
6
4
2
3
3
2
3
2
2
2
2
2
-
4
CH ); 0.96 (t, J ) 7.8 Hz, 3H, N-CH CH CH CH CH CH );
2
Cl
2
): 705 (4.5 × 10 ),
3
2
2
2
2
2
3
4
4
4
3
-0.61 and -0.88 (each br s, 1H, 2N-H). Mass calcd for
47 (1.2 × 10 ), 549 (2.3 × 10 ), 510 (1.0 × 10 ), 483 (8 × 10 ),
5 1
3
17 (1.2 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
, δ
40 47
C H N O : 661.3621. Found: 661. 3624.
5
4
6
ppm): 9.62 (s, 1H, for 10H); 9.37 (s, 1H, for 5H); 8.58 (s, 1H,
for 20H); 7.91 (dd, J ) 17.4, 11.2 Hz, 1H, 3CHdCH ); 6.28 (d,
J ) 17.4,1H, 3CHdCH ); 6.15 (d, J ) 11.2,1H, 3CHdCH );
.40 (m, 17H); 4.46 (m, 2H, N-CH CH CH CH CH CH CH
CH CH CH ); 4.35 (q, J ) 7.4 Hz, 1H for 18H); 3.83 (s, 3H,
2CH ); 3.62 (q, 2H, 8 CH
H, 2CH ); 3.12 (s, 3H, 7CH
Ch lor in -p -13-h exylam ide-15-m eth oxycar bon yl-17-pr o-
p ion ic Ester (5e) a n d 15-Hexyla m id e Isom er (6e). A
mixture of amide 3 and 4 (500 mg) was reacted with a large
excess of diazomethane and converted into a mixture of the
title compound and its isomer in quantitative yield. After
purification (silica column with 3% acetone in dichloromethane),
both isomers were isolated pure in 95% total yield (485 mg).
2
2
2
5
2
2
2
2
2
2
2
-
2
2
3
1
2
1
3
1
CH
1
3
2
); 3.56 (s, 3H, 17 CO
2 3
CH ); 3.35 (s,
3
3
); 2.68 and 2.40 (each m, 1H, 2 ×
1
2
2
7 H and 1 × 17 H); 1.99 (m, 3H, 1 × 17 H and N-CH
CH CH CH CH CH CH CH ); 1.76 (d, J ) 7.2 Hz, 3H,
8CH
2
CH
2
-
UV-vis (in CH
507 (0.107), 411 (1.000). H NMR (400 MHz, 3 mg/1 mL CDCl
δ ppm): 9.70, 9.59, and 8.77 (each s, 1H, for 5H, 10H and 20H);
8.03 (dd, J ) 17.4, 11.4 Hz, 1H, 3CHdCH ); 6.34 (d, J ) 17.4,
CH CH CH CH CH );
); 5.05 (m, 1H for 17H); 4.44
(m, 1H for 18H); 3.84 and 3.73 (each m, NHCH CH CH CH
); 3.46 and 3.45 (each
); 3.27 (s, 3H, 7CH ); 2.50-1.80
2 2
Cl , rel ꢀ): 666 (0.333), 615 (0.054), 543 (0.062),
1
2
2
2
2
2
2
2
3
3
,
2
3
); 1.67 (t, J ) 7.2 Hz, 3H, 8 CH
3
); 1.61-1.30 (m, total
CH CH CH ); 0.88 (t,
CH CH ); -0.14 and
: 717.4.
for 14H, N-CH
3
2
CH
CH
2
CH
2
CH
2
CH
CH
2
CH
CH
2
CH
CH
2
2
2
3
2
1
H, N-CH
2
CH
2
2
CH
2
CH
2
2
2
2
2
3
1H, 3CHdCH
6.14 (d, J ) 11.9, 1H, 3CHdCH
2
); 6.25 (m, 1H, 13 NHCH
2
2
2
2
2
3
-
0.17 (each br s, 1H, 2NH). Mass calcd for C44
H
55
N
5
O
4
2
Found: 717.8.
2
2
2
2
-
1
CH
2
CH
3
and 8 CH
2
); 3.61 (s, 3H, 12CH
and 2CH
CH CH
.72 (m, 6H, 18CH and 8 CH
3
P u r p u r in -18-N-d od ecylim id e (7i). Purpurin-18 methyl
ester 2 (500 mg) was reacted with 1-dodecylamine (1.0 mL)
by following method 2, and the corresponding imide was
2
s, 3H, 17 CO
(
1
2
CH
m, 6H, NHCH CH
3
3
3
1
2
2
2
2
2
CH
2
CH
3
, 2 × 17 H and 2 × 17 H);
2
2
isolated in 60% yield (385 mg). UV-vis (in CH
2
Cl
2
): 705 (4.5
3
3
); 1.50-1.10 (m, N-CH -
4
4
4
4
CH CH CH CH CH ); 0.93 (m, N-CH CH CH CH CH CH );
×
10 ), 647 (1.2 × 10 ), 549 (2.3 × 10 ), 510 (1.0 × 10 ), 483 (8
2
2
2
2
3
2
2
2
2
2
3
3
5
1
-1.34 and -1.56 (each br s, 1H, 2N-H). Mass calcd for
×
10 ), 417 (1.2 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
,
C
41
H
51
N
5
O
5
: 693.4. Found: 694.8.
δ ppm): 9.62 (s, 1H, for 10H); 9.37 (s, 1H, for 5H); 8.59 (s, 1H,
3
for 20H); 7.91 (dd, J ) 17.4, 11.2 Hz, 1H, 3CHdCH
J ) 17.4,1H, 3CHdCH ); 6.17 (d, J ) 11.2,1H, 3CHdCH
.40 (m, 17H); 4.46 (m, 2H, N-CH CH CH CH CH CH CH
CH CH CH CH CH ); 4.35 (q, J ) 7.4 Hz, 1H for 18H); 3.83
s, 3H, 12CH ); 3.62 (q, 2H, 8 CH
.35 (s, 3H, 2CH ); 3.12 (s, 3H, 7CH
2
); 6.29 (d,
17 -(Hexyla m id e)p u r p u r in -18-N-h exylim id e (14). The
title compound 14 was isolated as a byproduct from the above
2
2
);
5
2
2
2
2
2
2
2
-
reaction mixture, mainly containing purpurin-18-N-hexylimide
4
2
2
2
2
3
9e. Yield: 10% (63 mg). UV-vis (in CH
2
Cl
2
): 705 (4.5 × 10 ),
1
2
4
4
4
3
(
3
1
3
2
); 3.56 (s, 3H, 17 CO
2
CH
3
);
647 (1.2 × 10 ), 549 (2.3 × 10 ), 510 (1.0 × 10 ), 483 (8 × 10 ),
5 1
3
3
3
); 2.68 and 2.40 (each m,
417 (1.2 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
, δ ppm):
1
2
2
H, 2 × 17 H and 1 × 17 H); 1.99 (m, 3H, 1 × 17 H and
9.58 (s, 1H, for 10H); 9.33 (s, 1H, for 5H); 8.57 (s, 1H, for 20H);

3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1553
7
.88 (dd, J ) 17.4, 11.2 Hz, 1H, 3CHdCH
CH CH CH CH CH ); 6.28 (d, J ) 17.4,1H, 3CHd
); 6.14 (d, J ) 11.2, 1H, 3CHdCH ); 5.27 (m, 17H); 4.46
m, 2H, N-CH CH CH CH CH CH ); 4.41 (q, J ) 7.3 Hz, 1H
for 18H); 3.80 (s, 3H, 12CH ); 3.63 (q, J ) 7.8 Hz, 2H, 8 CH
); 3.14 (s, 3H, 7CH ); 2.72 and 2.44 (each m,
2
); 6.97 (br s, 1H,
3-(1-(H ep t yloxy)et h yl)p u r p u r in -18-N-h exylim id e-17-
p r op ion ic Ester (37). Purpurin-18-N-hexylimide 9e (400 mg)
was converted into the related bromo derivative, which when
reacted with 1-heptanol produced the title compound in 70%
yield (330 mg) as a sticky solid after purification (alumina
NHCH
CH
(
2
2
2
2
2
3
2
2
2
2
2
2
2
3
1
3
2
);
3
1
.35 (s, 3H, 2CH
3
1
3
grade II column, eluted with 25% n-hexanes in CH
2
Cl
2
). UV-
2
2
4
3
H +2H, 2 × 17 H and 1 × 17 H); 2.00 (m, 3H, 1 × 17 H and
CH CH CH CH CH ); 1.72 (d, J ) 7.2 Hz, 3H, 18CH );
.66 (t, J ) 7.2 Hz, 3H, 8 CH
N-CH CH CH CH CH CH
CH ); 0.96 (t, J ) 7.1 Hz, 3H, N-CH
.87 (t, J ) 6.9 Hz, 3H, NHCH CH CH
0.14 (each br s, 1H, 2N-H). Mass calcd for C45
30.5. Found: 731.3 (M + 1).
2-F or m ylp u r p u r in -18-N-h exylim id e-17-p r op ion ic Es-
vis (in CH
2
Cl
× 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz,
3 mg/1 mL CDCl , δ ppm): 9.77 (s, 1H, for 10H); 9.65 (s, 1H,
for 5H); 8.55 (s, 1H, for 20H); 5.79 (q, J ) 6.8 Hz, 1H, 3 H);
5.40 (m, 17H); 4.46 (m, 2H, N-CH CH CH CH CH CH ); 4.35
(q, J ) 7.2 Hz, 1H for 18H); 3.84 (s, 3H, 12CH ); 3.67 (q, 2H,
CH ); 3.56 (s,
); 3.20 (s, 3H, 7CH ); 2.67,
.43, and 2.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.06 (m,
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81
4
3
5
1
N-CH
1
2
2
2
2
2
3
3
2
3
); 1.63-1.26 (m, total for 16H,
3
1
2
2
2
2
2
3
and NHCH
CH
CH
2
CH
CH
CH
2
CH
CH
CH
2
CH
CH
2
CH
CH
2
-
);
3
2
2
2
2
2
3
2
2
2
2
2
3
0
-
7
2
2
2
2
2
3
); 0.15 and
3
1
H
58
N
6
O
3
:
8 CH
2
); 3.60 (m, 2H, O-CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
3
2
3H, 17 CO
2
CH
3
); 3.31 (s, 3H, 2CH
3
1
3
2
2
1
1
2
J ) 6.7, 2.7 Hz, 3H, 3 CH
N-CH CH CH CH CH CH
.64 (t, J ) 7.2 Hz, 3H, 8 CH
3
); 1.99 (m, 2H + 1H, 1 × 17 H and
); 1.74 (d, J ) 7.2 Hz, 3H, 18CH );
); 1.61-1.19 (m, total for 16H,
ter (12). The title compound was isolated from the reaction
mixture mainly containing purpurin-18-N-hexylimide 9e as a
2
2
2
2
2
3
3
2
1
3
byproduct in 5% yield (30 mg). UV-vis (in CH
2
Cl
10 ), 660 (4.39 × 10 ), 582 (4.50 × 10 ), 420 (2.72 × 10 ). H
NMR (400 MHz, 5 mg/1 mL CDCl , δ ppm): 11.84 (s, 1H, 12-
CHO), 10.19 (s, 1H, 5-H), 8.79 (s, 1H, 10-H), 8.24 (s, 1 H, 20-
H), 7.69 (dd, 1H, J ) 18.8, 12.5 Hz, 3CHdCH ), 6.24 (d, 1H, J
18.8, 3CHdCH ), 6.18 (d, 1H, J ) 12.5, 3CHdCH ), 5.19 (d,
H, J ) 8.6, 17-H), 5.44 (t, 2H, J ) 7.8, N-CH CH CH CH
CH CH ), 4.18 (q, H, J ) 8.0, 18H), 3.60 (s, 3H, 17 CO CH
.43 (q, 2H, J ) 7.6, 8 CH ), 2.92 (s, 3H,
CH
), 2.70 and 2.41 (m, 1H + 2H, 2 × 17 H, and 1 × 17 H),
.95 (m, 5H, 1 × 17 H and N-CH
2
): 717 (1.15
4
3
3
4
1
O-CH CH CH CH CH CH CH and N-CH CH CH CH CH -
×
2
2
2
2
2
2
3
2
2
2
2
2
CH
O-CH
3
); 0.95 (t, 3H, N-CH
2
CH
2
CH
2
CH
2
CH
2
3
CH ); 0.78 (m, 3H,
3
2
CH CH CH CH
2
2
2
2
CH
2
CH
3
); -0.08 and -0.17 (each br
63 5 5
s, 1H, 2NH). Mass calcd for C47
M + 1).
3-(1-(H ep t yloxy)-2-b r om oet h yl)p u r p u r in -18-N-h exyl-
H N O : 777.5. Found: 778
2
(
)
1
2
2
2
2
2
2
2
-
2
3
2
3
),
im id e-17-p r op ion ic Acid (15). The title compound was
isolated as a byproduct in 10% yield (55 mg) from the reaction
mixture containing mainly purpurinimide 37 as the major
1
3
3
1
2
), 3.21 (s, 3H, 7CH
3
1
2
3
2
4
2
CH
2
CH
2
CH
2
CH
), 1.65-1.17
), 0.95 (t, 3H, N-CH CH
), -0.15 and -0.46 (each br s, 2H, 21- and
3NH). Mass calcd for C40 : 675.3. Found: 676.1 (M + 1).
2-(Hydr oxym eth yl)pu r pu r in -18-N-h eptylim ide-17-pr o-
2
CH
3
), 1.71
product. UV-vis (in CH
2
Cl
2
): 699 (4.25 × 10 ), 642 (7.60 ×
2
3
4
3
5
1
(
(
d, 3H, J ) 8.0, 18Me), 1.58 (t, 3H, J ) 7.6, 8 CH
m, 6H, N-CH CH CH CH CH CH
CH CH CH
3
10 ), 543 (1.91 × 10 ), 507 (6.92 × 10 ), 414 (1.28 × 10 ) H
NMR (400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.72 (s, 1H, for
10H); 9.67 (s, 1H, for 5H); 8.58 (s, 1H, for 20H); 5.82 (q, J )
2
2
2
2
2
3
2
2
-
3
CH
2
2
2
3
1
2
H
45
N
5
O
5
6.8 Hz, 1H, 3 H); 5.40 (m, 17H); 4.46 (m, 2H, N-CH
2
CH
2 2
CH -
CH
2
CH
2
CH
3
); 4.35 (m, 1H for 18H); 4.34 and 4.07 (each m,
1
1
1
1
H, 3 CH
2
Br); 3.84 (s, 3H, 12CH
3
); 3.67 (q, 2H, 8 CH
CH ); 3.56 (s, 3H, 17 CO
); 3.20 (s, 3H, 7CH ); 2.67, 2.43 and
2
); 3.60
p ion ic Ester (13). The title compound was isolated from the
reaction mixture consisting of mainly purpurin-18-N-heptyl-
imide 7f as a byproduct in 5% yield (30 mg).UV-vis (in CH
Cl
2
(
m, 2H, O-CH
2
CH
2
CH
2
CH
3
2
CH
2
CH
2
3
2
-
CH ); 3.31 (s, 3H, 2CH
3
3
2
-
1
2
4
4
4
2.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 1.99 (m, 2H + 1H,
2
): 705 (4.5 × 10 ), 648 (1.2 × 10 ), 555 (2.3 × 10 ), 483 (8
3 5 1
3
2
1 × 17 H and N-CH CH CH CH CH CH ); 1.74 (d, J ) 7.2
2
2
2
2-
2
3
×
10 ), 420 (1.2 × 10 ). H NMR (400 MHz, 5 mg/1 mL CDCl
,
2
Hz, 3H, 18CH
m, total for 16H, O-CH
CH CH CH CH CH ); 0.95 (t, 3H, N-CH
.78 (m, 3H, O-CH CH CH CH CH CH
N-H). Mass calcd for: C47
3
); 1.64 (t, J ) 7.2 Hz, 3H, 8 CH
CH CH CH CH CH CH
CH
); -0.25 (br s, 2H,
3
); 1.61-1.19
and N-CH
3
CH CH CH );
δ ppm): 9.53, (s, 1H, for 10H); 9.22 (s, 1H, for 5H); 8.47 (s,
(
2
2
2
2
2
2
3
2
-
1
(
6
CH
3
2
H, for 20H); 7.84 (dd, J ) 17.4, 11.2 Hz, 1H, 3CHdCH
d, J ) 17.4,1H, 3CHdCH ); 6.16 (d, J ) 11.2,1H, 3CHdCH
OH); 5.32 (m, 17H); 4.46 (m, 2H, N-CH
CH CH ); 4.31 (q, J ) 7.3 Hz, 1H for 18H);
); 3.57 (s, 3H, 17 CO
); 3.11 (s, 3H, 7CH
); 2.68 and 2.39 (each m, 1H, 2 × 17 H
2
); 6.27
);
2
2
2
2
3
2
2
CH
2
2
2
2
2
2
0
2
2
2
2
2
2
CH
3
.06 (s, 2H, 12CH
CH CH CH
.59 (q, 2H, 8 CH
CH
2
2
-
H
62
N
5
O
5
Br: 855.4. Found: 857.5
2
2
2
2
2
3
1
2
(M+2).
2
2 3
CH ); 3.31 (s, 3H,
1
3
3
3-(1-(Meth yloxy)eth yl)p u r p u r in -18-N-m eth ylim id e-17-
p r op ion ic Ester (16). Purpurin-18-N-methylimide 9a (50 mg)
was converted into the related bromo derivative, which when
reacted with anhydrous methanol produced the title compound
2
2
and 1 × 17 H); 1.98 (m, 3H, 1 × 17 H and N-CH
CH CH CH CH ); 1.74 (d, J ) 7.2 Hz, 3H, 18CH ); 1.64 (t, J
7.2 Hz, 3H, 8 CH ); 1.55 and 1.37 (each m, total for 8H,
N-CH CH CH CH CH CH CH ); 0.92 (t, 3H, N-CH CH CH
CH CH CH CH ); 0.47 and 0.27 (each br s, 1H, 2NH). Mass
calcd for C41 : 691.4. Found: 692.2 (M + 1).
2 2 2
CH CH -
2
2
2
3
3
2
)
3
2
2
2
2
2
2
3
2
2
2
-
in 60% yield (32 mg) after purification (silica plate with 2%
4
2
2
2
3
MeOH in CH
2
Cl
2
). UV-vis (in CH
2
Cl
2
): 699 (4.53 × 10 ), 642
3
4
3
H
49
N
5
O
5
(7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28 ×
5
1
1
9
0 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
, δ ppm): 9.67 and
Gen er a l Meth od for th e Syn th esis of Alk yl Eth er
Der iva tives of P u r p u r in -18-N-a lk ylim id es-17-p r op ion ic
Ester . For the preparation of alkyl ether derivatives, purpurin-
.65 (each s, 1H, for 10H and 5H); 8.55 (s, 1H, for 20H); 5.74
1
(
q, J ) 6.8 Hz, 1H, 3 H); 5.35 (m, 1H for 17H); 4.36 (q, J ) 7.3
Hz, 1H for 18H); 3.84 (s, 3H, 12CH ); 3.78 (s, 3H, N-CH );
); 3.55
); 3.20 (s, 3H,
1
8-N-alkylimide 9 (100 mg) was reacted with 30% hydrobromic
3
3
1
2
3
.68 (q, J ) 7.8 Hz, 2H, 8 CH
2
); 3.58 (s, 3H, 17 CO
2 3
CH
acid/acetic acid (1.5 mL) using a rubber septum and the
reaction stirred at room temperature for 3 h. After evaporating
the acids to dryness under high vacuum (0.1 mmHg), the
residue was reacted with the desired alcohol (excess). Dry
dichloromethane (10 mL) and anhydrous potassium carbonate
1
(splitting s, 3H, 3 OCH
3
); 3.33 (s, 3H, 2CH
3
1
7
CH
3
); 2.72, 2.41 and 1.99 (each m, 1H + 2H + 1H, 2 × 17 H
2
1
and 2 × 17 H); 2.08 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
); 1.73 (d,
); -0.12
2
J ) 7.0 Hz, 3H, 18CH
3
); 1.68 (t, J ) 7.0 Hz, 3H, 8 CH
3
1
(br s, 2H, 2NH). Anal. Calcd for C36
H
41
N
5
O
5
2 2
‚ / H O: C, 68.32;
(40 mg) were then added. The reaction mixture was stirred
H, 6.69; N, 10.07. Found: C, 68.34; H, 6.62; N, 10.69.
under a nitrogen atmosphere for 45 min. It was then diluted
with dichloromethane (200 mL) and reacted with diazo-
methane. Evaporation of the solvent gave a residue that was
chromatographed over alumina column (Gr III) and eluted
with dichloromethane/hexane (ratio varies). The major frac-
tion was collected. Evaporation of the solvent gave the desired
alkyl ether derivative. By following the methodology as
discussed above, a series of alkyl ether derivatives were
synthesized. Most alkyl ether analogues, especially those with
long carbon chains, were obtained as sticky solids and could
not be crystallized. The yield, UV-vis spectrum, mass spec-
3-(1-(Hexyloxy)et h yl)p u r p u r in -18-N-m et h ylim id e-17-
p r op ion ic Ester (33). Purpurin-18-N-methylimide 9a (100
mg) was converted into the related bromo derivative, which
when reacted with 1-hexanol produced the title compound in
70% yield (82 mg) as a sticky solid (alumina grade II column,
eluted with 25% n-hexanes in CH
2
Cl
2
). UV-vis (in CH
2 2
Cl ):
4
3
4
699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54
3
5
1
× 10 ), 414 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
,
δ ppm): 9.77 (s, 1H, for 10H); 9.65 (s, 1H, for 5H); 8.54 (s, 1H,
1
for 20H); 5.79 (q, J ) 6.8 Hz, 1H, 3 H); 5.35 (m, 1H for 17H);
1
troscopic data, and H NMR of various alkyl ethers were as
follows:
4.36 (q, J ) 7.3 Hz, 1H for 18H); 3.842 and 3.838 (each s, 3H,
1
12CH
3
and N-CH
3
); 3.67 (m, 4H, 8 CH
2
2 2 2
and O-CH CH CH -

1
554 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Zheng et al.
2
CH
2
CH
2
CH
3
); 3.59 (s, 3H, 17 CO
2
CH
3
); 3.31 (s, 3H, 2CH
3
); 3.20
was converted into the related bromo derivative, which when
reacted with anhydrous methanol produced the title compound
in 80% yield (58 mg) after purification over silica column,
(s, 3H, 7CH
3
); 2.71, 2.41 and 1.99 (each m, 1H + 2H + 1H, 2
1
2
1
×
17 H and 2 × 17 H); 2.07 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
);
);
2
1
1
.75 (d, J ) 7.0 Hz, 3H, 18CH
3
); 1.64 (t, J ) 7.0 Hz, 3H, 8 CH
3
eluting with 2% acetone in CH
2
Cl
2
. UV-vis (in CH
2 2
Cl ): 699
4
3
4
.55-1.25 (m, total for 8H, O-CH
CH CH CH CH CH
H). Mass calcd for C41 : 693.4. Found: 694.5 (M + 1).
Anal. Calcd for C41 O: C, 70.04; H, 7.46; N, 9.96.
2
CH
2 2 2 2 3
CH CH CH CH ); 0.75
(4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 ×
3
5
1
(m, 3H, O-CH
2
2
2
2
2
3
); -0.11 (br s, 2H, 2N-
10 ), 414 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
,
H
N
51
N
5
O
5
δ ppm): 9.67 and 9.61 (each s, 1H, for 10H and 5H); 8.54 (s,
1
1
H
51
5
O
5
‚ /
2
H
2
1H, for 20H); 5.74 (q, J ) 6.8 Hz, 1H, 3 H); 5.36 (m, 1H for
Found: C, 70.10; H, 7.37; N, 9.52.
-(1-(Dod ecyloxy)et h yl)p u r p u r in -18-N-m et h ylim id e-
7-p r op ion ic Ester (42). Purpurin-18-N-methylimide 9a (50
17H); 4.56 (m, 2H, N-CH
2
CH
2
CH
3
); 4.36 (q, J ) 7.3 Hz, 1H
1
for 18H); 3.84 (s, 3H, 12CH
3
); 3.66 (q, J ) 7.8 Hz, 2H, 8 CH
2
);
.56 (s, 3H, 17 CO ); 3.36
3
s, 3H, 2CH ); 3.20 (s, 3H, 7CH ); 2.72, 2.41, and 1.99 (each
3
2
1
3
2 3 3
CH ); 3.53 (splitting s, 3H, 3 OCH
1
(
3
mg) was converted into the related bromo derivative, which
when reacted with 1-dodecanol produced the title compound
in 60% yield (40 g) as a sticky solid after purification (silica
1
2
m, 1H + 2H + 1H, 2 × 17 H and 2 × 17 H); 2.08 (m, J ) 6.7,
1
2
.7 Hz, 3H, 3 CH
3
2 2 3
); 2.02 (m, 2H, N-CH CH CH ); 1.76 (d, J
2
)
7.0 Hz, 3H, 18CH
J ) 6.3 Hz, 3H, N-CH CH CH ); -0.12 (br s, 2H, 2N-H).
38 45 5 5
HRMS calcd for C H N O : 651.3421. Found 651.3445.
3
3
); 1.67 (t, J ) 7.0 Hz, 3H, 8 CH ); 1.19 (t,
plate, with 2% MeOH in CH
2
Cl
2
2
). UV-vis spectrum (in CH -
4
3
4
Cl
7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL
CDCl , δ ppm): 9.76 (s, 1H, for 10H); 9.65 (s, 1H, for 5H); 8.53
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507
2
2
3
3
5
1
(
3
3-(1-(P r op yloxy)eth yl)p u r p u r in -18-N-p r op ylim id e-17-
p r op ion ic Ester (18). Purpurin-18-N-propylimide 9c (70 mg)
was converted into the related bromo derivative, which when
reacted with 1-propanol produced the title compound in 75%
yield (57 mg) after purification on a silica column, eluting with
1
(
1
3
s, 1H, for 20H); 5.78 (q, J ) 6.8 Hz, 1H, 3 H); 5.35 (m, 1H for
7H); 4.36 (q, J ) 7.3 Hz, 1H for 18H); 3.84 (s, 3H, 12CH
3
);
1
.68 (m, 4H, 8 CH
CH CH CH ); 3.59 (s, 3H, 17 CO
.20 (s, 3H, 7CH
2
and O-CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
-
2
CH
2
2
2
3
2
CH
3
); 3.31 (s, 3H, 2CH
3
);
4
3
1
3
3
3
); 2.71, 2.41 and 1.99 (each m, 1H + 2H +
2% acetone in CH Cl . UV-vis (in CH Cl ): 699 (4.53 × 10 ),
2
2
2
2
1
2
3
4
3
H, 2 × 17 H and 2 × 17 H); 2.06 (m, J ) 6.7, 2.7 Hz, 3H,
642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28
1
5
1
CH
3
2
); 1.73 (d, J ) 7.0 Hz, 3H, 18CH
3
); 1.68 (t, J ) 7.0 Hz,
× 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.77
3
H, 8 CH
3
); 1.55-1.10 (m, total for 20H, O-CH
2
CH
2
CH
2
CH
CH
2
-
-
(s, 1H, for 10H); 9.66 (s, 1H, for 5H); 8.54 (s, 1H, for 20H);
1
CH
CH
2
CH
CH
2
CH
2
CH
CH
2
CH
CH
2
CH
CH
2
CH
2
CH
CH
3
); 0.83 (m, 3H, O-CH
CH
2
2
5.80 (q, J ) 6.8 Hz, 1H, 3 H); 5.40 (m, 1H for 17H); 4.43 (m,
2
2
CH
2
2
2
2
CH
2
2
2
5
CH
3
); -0.11 (br s, 2H,
2H, N-CH CH CH ); 4.34 (q, J ) 7.3 Hz, 1H for 18H); 3.84
2
2
3
1
2
N-H). Mass calcd for C47
H
63
N
5
O
:
777.5. Found: 779.0
(s, 3H, 12CH ); 3.66 (m, 4H, 8 CH and O-CH CH CH ); 3.56
3
2
2
2
3
+
2
(M +1).
2 3 3 3
(s, 3H, 17 CO CH ); 3.31 (s, 3H, 2CH ); 3.20 (s, 3H, 7CH );
1
2
3
-(1-(Eth yloxy)eth yl)pu r pu r in -18-N-eth ylim ide-17-p r o-
2.66, 2.43, 2.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.06
1
2
p ion ic Ester (17). Purpurin-18-N-ethylimide 9b (100 mg) was
converted into the related bromo derivative, which when
reacted with ethanol produced the title compound in 60% yield
(m, J ) 6.7, 2.7 Hz, 3H, 3 CH
N-CH CH CH
7.0 Hz, 3H, 8 CH
6.3 Hz, 3H, N-CH
3
); 2.02 (m, 3H, 1 × 17 H and
2
2
3
); 1.76 (d, J ) 7.0 Hz, 3H, 18CH
3
3
); 1.67 (t, J )
); 1.19 (t, J )
2
3
); 1.26 (m, 2H, O-CH
2
CH
2
CH
(
65 mg) after purification over alumina grade II column eluting
2
CH CH
2
3
2 2 3
); 0.96 (m, 3H, O-CH CH CH );
4
with CH
×
2
Cl
10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H
NMR (400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.79 (s, 1H, for
0H); 9.66 (s, 1H, for 5H); 8.56 (s, 1H, for 20H); 5.83 (q, J )
2
.UV-vis (in CH
2
Cl
2
): 699 (4.53 × 10 ), 642 (7.35
-0.08 and -0.17 (each br s, 1H, 2NH). HRMS calcd for
: 679.3734. Found: 679.3755.
3-(1-(H exyloxy)et h yl)p u r p u r in -18-N-p r op ylim id e-17-
3
4
3
5
1
40 49 5 5
C H N O
3
1
6
CH
p r op ion ic Ester (27). Purpurin-18-N-propylimide 9c (70 mg)
was converted into the related bromo derivative, which when
reacted with 1-hexanol produced the title compound in 60%
yield (49 mg) after purification on a silica column, eluting with
1
.8 Hz, 1H, 3 H); 5.39 (m, 1H for 17H); 4.56 (m, 2H, N-CH
2
-
3
); 4.37 (q, J ) 7.3 Hz, 1H for 18H); 3.84 (s, 3H, 12CH
3
);
);
1
2
3
3
.7 (m, 4H, 8 CH
2
and O-CH
2 3 2
CH ); 3.58 (s, 3H, 17 CO CH
3
.34 (s, 3H, 2CH ); 3.21 (s, 3H, 7CH
3
3
); 2.72, 2.41 and 2.00 (each
1% acetone in CH Cl . UV-vis (in CH Cl ): 699 (4.53 × 10
4
),
2
2
2
2
1
2
3
4
3
m, 1H + 2H + 1H, 2 × 17 H, and 2 × 17 H); 2.07 (m, J ) 6.7,
642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28
1
5
1
2
.7 Hz, 3H, 3 CH
3
); 1.76 (d, J ) 7.0 Hz, 3H, 18CH
3
); 1.69 (t, J
× 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.77
3
2
)
1
(
7.0 Hz, 3H, 8 CH
.36 (m, J ) 7.1, 5.2 Hz, 3H, O-CH
each br s, 1H, 2NH). Mass calcd for C38
Found: 652.2 (M + 1). Anal. Calcd for C38
9.05; H, 7.02; N, 10.60. Found: C, 69.13; H, 6.93; N, 10.33.
-(1-(Hexyloxy)eth yl)pu r pu r in -18-N-eth ylim ide-17-pr o-
3
); 1.58 (t, J ) 6.3 Hz, 3H, N-CH
CH ); -0.07 and -0.15
651.3.
O: C,
2
CH
3
);
(s, 1H, for 10H); 9.66 (s, 1H, for 5H); 8.54 (s, 1H, for 20H);
1
2
3
5.79 (q, J ) 6.8 Hz, 1H, 3
H); 5.40 (m, 1H for 17H); 4.43 (m,
45 5 5
H N O :
2H, N-CH CH CH ); 4.34 (q, J ) 7.3 Hz, 1H for 18H); 3.84
2
2
3
1
1
H
45
N
5
O
5
‚ /
2
H
2
(s, 3H, 12CH ); 3.67 (m, 4H, 8 CH and O-CH CH CH CH -
3
2
2
2
2
2
6
2
2 3 3
CH CH ); 3.56 (s, 3H, 17 CO CH ); 3.36 (s, 3H, 2CH ); 3.20
2
3
1
3
(s, 3H, 7CH
3
); 2.67, 2.42, and 2.33 (each m, 1H, 2 × 17 H and
2
1
p ion ic Ester (26). Purpurin-18-N-ethylimide 9b (100 mg) was
converted into the related bromo derivative, which when
reacted with 1-hexanol and purified by following the procedure
as described for the foregoing compound produced the title
1 × 17 H); 2.06 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
); 2.02 (m, 3H,
2
1 × 17 H and N-CH
2 2 3
CH CH ); 1.75 (d, J ) 7.0 Hz, 3H,
2
18CH
O-CH
CH CH
3
); 1.69 (t, J ) 7.0 Hz, 3H, 8 CH
CH CH CH CH CH ); 1.19 (t, J ) 6.3 Hz, 3H, N-CH
); 0.78 (m, 3H, O-CH CH CH CH CH CH ); -0.08
3
); 1.46-1.16 (m, 2H,
2
2
2
2
2
3
2
-
product in 65% yield (75 mg) as a sticky solid. UV-vis (in CH
2
-
2
3
2
2
2
2
2
3
4
3
4
Cl
7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL
CDCl , δ ppm): 9.78 (s, 1H, for 10H); 9.66 (s, 1H, for 5H); 8.54
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507
55 5 5
and -0.17 (each br s, 1H, 2NH). HRMS calcd for C43H N O :
3
5
1
(
721.4203. Found: 721.4222.
3
3
-(1-(Decyloxy)et h yl)p u r p u r in -18-N-p r op ylim id e-17-
1
(
1
1
s, 1H, for 20H); 5.80 (q, J ) 6.8 Hz, 1H, 3 H); 5.38 (m, 1H for
p r op ion ic Ester (43). Purpurin-18-N-propylimide 9c (100
mg) was converted into the related bromo derivative, which
when reacted with 1-decanol produced the title compound in
7H); 4.55 (m, 2H, N-CH
8H); 3.86 (s, 3H, 12CH ); 3.67 (m, 4H, 8 CH
CH CH CH CH ); 3.57 (s, 3H, 17 CO
CH ); 3.20 (s, 3H, 7CH ); 2.70, 2.39, and 2.00 (each m, 1H +
2 3
CH ); 4.36 (q, J ) 7.3 Hz, 1H for
1
3
2
and O-CH
2
-
2
CH
2
2
2
2
3
CH ); 3.32 (s, 3H,
2 3
6
0% yield (75 mg) as a sticky solid after purification on a
2
2
3
3
3
alumina grade II column, eluting with 25% n-hexanes in CH
2
-
1
2
H + 1H, 2 × 17 H and 2 × 17 H); 2.06 (m, J ) 6.7, 2.7 Hz,
4
3
Cl
5
(
2
.UV-vis (in CH
2
Cl
43 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR
400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.77 (s, 1H, for 10H);
.66 (s, 1H, for 5H); 8.55 (s, 1H, for 20H); 5.79 (q, J ) 6.8 Hz,
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ),
1
H, 3 CH
3
2
); 1.76 (d, J ) 7.0 Hz, 3H, 18CH
3
); 1.69 (t, J ) 7.0
4
3 5 1
Hz, 3H, 8 CH
3
); 1.58 (t, J ) 6.3 Hz, 3H, N-CH
CH CH CH CH CH
CH ); -0.06 and -0.16 (each br
: 707.4. Found: 707.4.
O: C, 71.24; H, 7.55; N, 9.89.
Found: C, 70.81; H, 7.54; N, 9.75.
-(1 -(Met h yloxy)et h yl)p u r p u r in -18 -N -p r op ylim id e
Meth yl Ester (25). Purpurin-18-N-propylimide 9c (70 mg)
2
CH
3
); 1.48-
3
1
3
.18 (m, total for 8H, O-CH
2
2
2
2
2
3
); 0.79 (m,
9
1
4
4
3
H, O-CH CH CH CH CH
2
2
2
2
2
3
1
H, 3 H); 5.40 (m, 1H for 17H); 4.43 (m, 2H, N-CH
.34 (q, J ) 7.3 Hz, 1H for 18H); 3.84 (s, 3H, 12CH
2
CH
2 3
CH );
s, 1H, 2NH). Mass calcd for C42
53 5 5
H N O
3
); 3.66 (m,
1
Anal. Calcd for C42
H
53
N
5
O
5
‚ /
2
H
2
1
H, 8 CH
2
and O-CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
3
);
);
2
.56 (s, 3H, 17 CO
2
CH
3
); 3.31 (s, 3H, 2CH
3
); 3.21 (s, 3H, 7CH
1
2
3
2.67, 2.44 and 2.31 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.07
1
2
(m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
); 2.02 (m, 3H, 1 × 17 H and

3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1555
N-CH
2
CH
2
CH
3
); 1.76 (d, J ) 7.0 Hz, 3H, 18CH
); 1.46-1.09 (m, total for 16H, O-CH
CH CH CH CH ); 1.19 (t, J ) 6.3 Hz, 3H,
); 0.79 (m, 3H, O-CH CH CH CH CH CH
); -0.08 and -0.17 (each br s, 1H, 2N-H).
Mass calcd for C47 : 777.5. Found: 779.0 (M + 1).
-(1-(Bu tyloxy)eth yl)pu r pu r in -18-N-bu tylim ide-17-pr o-
3
); 1.69 (t, J )
reacted with 1-propanol produced the title compound in 70%
2
7
.0 Hz, 3H, 8 CH
3
2
CH
2
-
yield (76 mg) as a sticky solid. UV-vis (in CH
2
Cl
2
): 699 (4.53
4
3
4
3
CH
N-CH
CH CH
2
CH
2
CH
2
CH
2
2
2
2
3
× 10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ),
5
1
2
CH
2
CH
3
2
2
2
2
2
2
-
414 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
, δ
2
2
CH
2
CH
3
ppm): 9.77 (s, 1H, for 10H); 9.65 (s, 1H, for 5H); 8.55 (s, 1H,
1
H
63
N
5
O
5
for 20H); 5.80 (q, J ) 6.8 Hz, 1H, 3 H); 5.41 (m, 17H); 4.46
(
m, 2H, N-CH
2
CH
2
CH
2
CH
2
CH
2 3
CH ); 4.35 (q, J ) 7.3 Hz, 1H
3
1
for 18H); 3.84 (s, 3H, 12CH
CH
3
); 3.67 (m, 4H, 8 CH
2
and O-CH
2
-
p ion ic Ester (19). Purpurin-18-N-butylimide 9d (100 mg) was
converted into the related bromo derivative, which when
reacted with 1-butanol produced the title compound in 70%
yield (78 mg) as a sticky solid obtained after purification on a
2
2
CH
3
); 3.56 (s, 3H, 17 CO
2
CH
3
); 3.31 (s, 3H, 2CH ); 3.20
3
1
(
1
1
s, 3H, 7CH
3
); 2.67, 2.44 and 2.32 (each m, 1H, 2 × 17 H and
2
1
× 17 H); 2.07 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
); 2.00 (m, 3H,
2
× 17 H and N-CH
2 2 2 2 3
CH CH CH2-CH CH ); 1.76 (d, J ) 7.2
2
alumina grade II column, eluting with 25% n-hexanes in CH -
2
4
3
Hz, 3H, 18CH ); 1.68 (t, J ) 7.2 Hz, 3H, 8 CH ); 1.60 and 1.46
Cl
5
(
2
. UV-vis (in CH
2
Cl
43 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR
400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.78 (s, 1H, for 10H);
.66 (s, 1H, for 5H); 8.55 (s, 1H, for 20H); 5.80 (q, J ) 6.8 Hz,
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ),
3
3
4
3
5
1
(m, total for 8H, N-CH CH CH CH CH CH and O-CH CH -
2
2
2
2
2
3
2
2
CH
CH
3
); 0.96 (m, 6H, O-CH
CH ); -0.07 and -0.16 (each br s, 1H, 2NH). Mass calcd
3
2
CH
2
CH
3
and N-CH
2
CH
2
CH
2
CH
2
-
3
9
1
2
1
for C H N O : 721.4. Found: 722.8 (M + 1).
H, 3 H); 5.41 (m, 1H for 17H); 4.48 (m, 2H, N-CH
2
CH
2
CH
2
-
43 55
5
5
CH
.66 (m, 4H, 8 CH
CO CH ); 3.31 (s, 3H, 2CH
3
); 4.36 (q, J ) 7.3 Hz, 1H for 18H); 3.84 (s, 3H, 12CH
3
);
3-(1-(Bu tyloxy)eth yl)pu r pu r in -18-N-h exylim ide-17-pr o-
p ion ic Ester (35). Purpurin-18-N-hexylimide 7e (80 mg) was
converted into the related bromo derivative, which when
reacted with 1-butanol produced the title compound in 60%
yield (53 mg) as a sticky solid. UV-vis (in CH Cl ): 699 (4.53
1
2
3
2
and O-CH
2
CH
2
CH
2
CH
3
); 3.57 (s, 3H, 17 -
); 2.68, 2.45,
2
3
3
); 3.19 (s, 3H, 7CH
3
1
2
2
2
.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.06 (m, J ) 6.7,
1
2
.7 Hz, 3H, 3 CH
CH
3
); 1.99 (m, 3H, 1 × 17 H and N-CH
2 2
CH -
2
2
4
3
4
3
CH
H, 8 CH
O-CH CH
CH CH ); 0.88 (m, 3H, O-CH
each br s, 1H, 2NH). Mass calcd for C42
Found: 707.7 (M + 1). Anal. Calcd for C42
1.24; H, 7.55; N, 9.89. Found: C, 70.80; H, 7.56; N, 9.52.
-(1-(Hexyloxy)eth yl)pu r pu r in -18-N-bu tylim ide-17-pr o-
2
3
); 1.77 (d, J ) 7.0 Hz, 3H, 18CH
3
); 1.70 (t, J ) 7.0 Hz,
× 10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ),
2
5
1
3
3
); 1.66-1.45 (m, 6H, N-CH
CH CH ); 1.10 (t, J ) 6.3 Hz, 3H, N-CH
CH CH CH ); -0.07 and -0.16
707.7.
O: C,
2
CH
2
CH
2
CH
3
and
414 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl , δ
3
2
2
2
3
2
CH
2
-
ppm): 9.77 (s, 1H, for 10H); 9.65 (s, 1H, for 5H); 8.55 (s, 1H,
1
2
3
2
2
2
3
for 20H); 5.80 (q, J ) 6.8 Hz, 1H, 3 H); 5.41 (m, 17H); 4.45
(
H
53
N
5
O
‚ /
5
:
(m, 2H, N-CH CH CH CH CH CH ); 4.35 (q, J ) 7.3 Hz, 1H
2
2
2
2
2
3
1
1
H
53
N
5
O
5
2
H
2
for 18H); 3.84 (s, 3H, 12CH ); 3.67 (m, 4H, 8 CH and O-CH -
3
2
2
2
7
2 2 3 2 3 3
CH CH CH ); 3.56 (s, 3H, 17 CO CH ); 3.33 (s, 3H, 2CH ); 3.20
1
3
(s, 3H, 7CH
3
); 2.67, 2.44 and 2.32 (each m, 1H, 2 × 17 H and
2
1
p ion ic Ester (28). Purpurin-18-N-butylimide 9d (100 mg) was
converted into the related bromo derivative, which when
reacted with 1-hexanol produced the title compound in 65%
1 × 17 H); 2.07 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
); 2.00 (m, 3H,
CH CH CH CH CH ); 1.76 (d, J ) 7.2
2
1 × 17 H and N-CH
2 2 2 2 2 3
2
Hz, 3H, 18CH
(m, total for 10H, N-CH
CH CH ); 0.96 (t, 3H, N-CH
3H, O-CH CH CH CH ); 0.24 and 0.15 (each br s, 1H, 2N-
H). Mass calculated for C44 : 735.4. Found: 736.9.
3
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH
CH CH CH CH CH and O-CH
CH CH CH CH CH ); 0.88 (m,
3
); 1.65-1.37
yield (75 mg) as a sticky solid. UV-vis (in CH
2
Cl
2
): 699 (4.53
2
2
2
2
2
3
2
CH -
2
4
3
4
3
×
10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ),
2
3
2
2
2
2
2
3
5
1
4
14 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
, δ
2
2
2
3
ppm): 9.77 (s, 1H, for 10H); 9.66 (s, 1H, for 5H); 8.55 (s, 1H,
57 5 5
H N O
1
for 20H); 5.79 (q, J ) 6.8 Hz, 1H, 3 H); 5.41 (m, 1H for 17H);
3-(1-(P en t yloxy)et h yl)p u r p u r in -18-N-h exylim id e-17-
p r op ion ic Ester (36). Purpurin-18-N-hexylimide 9e (80 mg)
was converted into the related bromo derivative, which when
reacted with 1-pentanol produced the title compound in 55%
yield (50 mg) as a sticky solid. UV-vis (in CH Cl ): 699 (4.53
4
1
CH
2
1
1
7
1
.47 (m, 2H, N-CH
8H); 3.85 (s, 3H, 12CH
CH CH CH CH ); 3.56 (s, 3H, 17 CO
CH ); 3.21 (s, 3H, 7CH
2
CH
2
CH
2 3
CH ); 4.36 (q, J ) 7.3 Hz, 1H for
1
3
); 3.68 (m, 4H, 8 CH
2
and O-CH
2
-
2
2
2
2
2
3
2 3
CH ); 3.31 (s, 3H,
3
3
); 2.67, 2.44, 2.31 (each m, 1H, 2 ×
1
3
2
2
1
2
4
3
4
3
7 H and 1 × 17 H); 2.07 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
);
× 10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ),
2
5
1
.99 (m, 3H, 1 × 17 H and N-CH
2
CH
2
CH
2
CH
3
); 1.76 (d, J )
414 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl , δ
3
2
.0 Hz, 3H, 18CH
3
); 1.69 (t, J ) 7.0 Hz, 3H, 8 CH
CH CH CH and O-CH
); 1.10 (t, J ) 6.3 Hz, 3H, N-CH
); 0.79 (m, 3H, O-CH CH2-CH CH CH CH
3
); 1.66-
ppm): 9.77 (s, 1H, for 10H); 9.65 (s, 1H, for 5H); 8.55 (s, 1H,
.19 (m, total for 10H, N-CH
2
2
2
3
2
CH
CH
2
-
-
for 20H); 5.80 (q, J ) 6.8 Hz, 1H, 3
1
H); 5.40 (m, 17H); 4.46
CH
CH
2
CH
CH
2
CH
2
CH
3
2
2
(m, 2H, N-CH CH CH CH CH CH ); 4.35 (q, J ) 7.3 Hz, 1H
2
2
2
2
2
3
); -0.07
for 18H); 3.84 (s, 3H, 12CH ); 3.65 (m, 4H, 8 CH and O-CH -
1
2
3
2
2
2
2
3
3
2
2
and -0.16 (each br s, 1H, 2NH). Mass calcd for C44
35.4. Found: 735.8.
-(1-(Met h yloxy)et h yl)p u r p u r in -18-N-h exylim id e-17-
H
57
N
5
O
5
:
2
2 3 3
CH CH CH CH ); 3.56 (s, 3H, 17 CO CH ); 3.32 (s, 3H, 2CH );
2
2
2
3
7
3.20 (s, 3H, 7CH ); 2.68, 2.44 and 2.32 (each m, 1H, 2 × 17
1
H
3
2
1
3
and 1 × 17 H); 2.06 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
); 2.00 (m,
2
p r op ion ic Ester (33). Purpurin-18-N-hexylimide 9e (100 mg)
was converted into the related bromo derivative, which when
reacted with anhydrous methanol produced the title compound
3H, 1 × 17 H and N-CH
2 2 2 2 2 3
CH CH CH CH CH ); 1.76 (d, J )
2
7.2 Hz, 3H, 18CH
1.23 (m, total for 12H, N-CH
O-CH CH CH CH CH ); 0.95 (t, 3H, N-CH
CH CH ); 0.84 (m, 3H, O-CH
3
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH
CH CH CH CH CH
CH CH
); 0.24 and 0.14
: 749.5.
3
); 1.65-
and
2
CH -
2
2
2
2
2
3
in 80% yield (84 mg) as a sticky solid. UV-vis (in CH
2
Cl
2
):
2
2
2
2
3
2
2
2
4
3
4
6
99 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54
2
3
2
CH
2
CH
2
CH
2
CH
3
3
5
1
×
10 ), 414 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
,
(each br s, 1H, 2N-H). Mass calcd for C45
Found: 751 (M + 1).
H
59 5 5
N O
δ ppm): 9.68 and 9.66 (each s, 1H, for 10H and 5H); 8.56 (s,
1
1
1
7
2
H, for 20H); 5.75 (q, J ) 6.8 Hz, 1H, 3 H); 5.41 (m, 1H for
7-H); 4.46 (m, 2H, N-CH CH CH CH CH CH ); 4.31 (q, J )
.3 Hz, 1H for 18H); 3.84 (s, 3H, 12CH ); 3.67 (q, J ) 7.7 Hz,
3
-(1-(Hexyloxy)eth yl)p u r p u r in -18-N-h exylim id ep r op i-
2
2
2
2
2
3
on ic Ester (20): Purpurin-18-N-hexylimide 9e (80 mg) was
converted into the related bromo derivative, which when
reacted with 1-hexanol produced the title compound in 40%
yield (37 mg) as a sticky solid after purification by preparative
3
1
2
1
H, 8 CH
2
); 3.57 (s, 3H, 17 CO
2
CH
3
); 3.55 (splitting s, 3H, 3 -
); 2.68, 2.43 and
OCH
3
); 3.31 (s, 3H, 2CH
3
1
); 3.21 (s, 3H, 7CH
3
2
2
2
CH
.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.07 (m, J ) 6.7,
plates eluting with 1% acetone in CH
2
Cl
2
2
. UV-vis (in CH -
1
2
.7 Hz, 3H, 3 CH
CH CH CH
7.2 Hz, 3H, 8 CH
CH CH CH CH CH ); 0.95 (t, 3H, N-CH
0.07 and -0.16 (each br s, 1H, 2NH). Mass calcd for C41
: 693.5. Found: 694.5. Anal. Calcd for C41 ‚H
3
); 1.99 (m, 3H, 1 × 17 H and N-CH
2
CH
); 1.64 (t, J
2
-
4
3
4
Cl
7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL
CDCl , δ ppm): 9.78 (s, 1H, for 10H); 9.65 (s, 1H, for 5H); 8.55
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507
); 1.74 (d, J ) 7.2 Hz, 3H, 18CH
3
3 5 1
2
2
2
3
(
2
)
3
); 1.61-1.31 (m, total for 6H, N-CH
2
-
);
3
CH CH CH CH CH
2
2
2
2
3
1
2
2
2
2
3
2
(
s, 1H, for 20H); 5.80 (q, J ) 6.8 Hz, 1H, 3 H); 5.40 (m, 17H);
-
N
51
H -
4
1
.46 (m, 2H, N-CH
H for 18H); 3.85 (s, 3H, 12CH
CH CH CH CH CH ); 3.57 (s, 3H, 17 CO
3H, 2CH ); 3.21 (s, 3H, 7CH ); 2.68, 2.44 and 2.32 (each m,
2
CH
2
CH
2
CH
2
CH
2 3
CH ); 4.36 (q, J ) 7.3 Hz,
O
5
H
51
N
5
O
5
2
O:
1
5
); 3.67 (m, 4H, 8 CH
and
2 3
CH ); 3.32 (s,
3
2
C, 69.16; H, 7.50; N, 9.84. Found: C, 69.25; H, 7.30; N, 9.45.
2
O-CH
2
2
2
2
2
3
3
-(1-(P r op yloxy)eth yl)p u r p u r in -18-N-h exylim id ep r o-
3
3
1
2
p ion ic Ester (34). Purpurin-18-N-hexylimide 9e (100 mg) was
converted into the related bromo derivative, which when
1H, 2 × 17 H and 1 × 17 H); 2.06 (m, J ) 6.7, 2.7 Hz, 3H,
1
2
3 CH
3
); 2.00 (m, 3H, 1 × 17 H and N-CH
2 2 2 2
CH CH CH2-CH -

1
556 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Zheng et al.
CH
8
CH
CH
CH
3
); 1.74 (d, J ) 7.2 Hz, 3H, 18CH
CH ); 1.61-1.16 (m, total for 14H, N-CH
and O-CH CH CH CH CH CH ); 0.95 (t, 3H, N-CH
CH CH CH CH ); 0.80 (m, 3H, O-CH CH CH CH CH
); -0.07 and -0.16 (each br s, 1H, 2NH). Mass calcd for
: 763.5. Found: 765.0 (M + 1).
-(1-(Octyloxy)eth yl)pu r pu r in -18-N-h exylim ide-17-pr o-
3
); 1.69 (t, J ) 7.2 Hz, 3H,
was converted into the related bromo derivative, which when
reacted with 1-dodecanol produced the title compound in 70%
yield (63 mg) as a sticky solid after purification on an alumina
2
3
2
CH
2
CH2-CH
2
CH
2
2
2
-
-
-
3
2
3
2
2
2
2
2
3
2
2
2
3
2
2
2
2
grade II column, eluting with 50% n-hexanes in CH
2
Cl
2
.UV-
4
3
vis (in CH
2
Cl
× 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz,
mg/1 mL CDCl , δ ppm): 9.77 (s, 1H, for 10H); 9.65 (s, 1H,
for 5H); 8.54 (s, 1H, for 20H); 5.79 (q, J ) 6.8 Hz, 1H, 3 H);
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81
4
3
5
1
46 61 5 5
C H N O
3
3
3
1
p ion ic Ester (38). Purpurin-18-N-hexylimide 9e (80 mg) was
converted into the related bromo derivative, which when
reacted with 1-octanol produced the title compound in 70%
5
.42 (m, 17H); 4.45 (m, 2H, N-CH
2
CH
2
CH
2
CH
2
CH
); 3.67 (m, 4H,
CH CH CH
CH ); 3.57 (s, 3H, 17 CO CH ); 3.33 (s, 3H, 2CH ); 3.20 (s, 3H,
2 3
CH ); 4.37
(q, J ) 7.3 Hz, 1H for 18H); 3.83 (s, 3H, 12CH
3
1
8
CH
2
and O-CH
2
CH
2
CH
2
2
CH
3
2
CH
2
CH
2
CH
2
CH
2
2
2
2
-
yield (67 mg) as a sticky solid.UV-vis (in CH
2
Cl
2
): 699 (4.53
2
4
3
4
3
×
10 ), 642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ),
3
3
1
5
1
7CH ); 2.68, 2.44 and 2.32 (each m, 1H, 2 × 17 H and 1 ×
4
14 (1.28 × 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
, δ
3
2
1
1
7 H); 2.06 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
); 2.00 (m, 3H, 1 ×
ppm): 9.78 (s, 1H, for 10H); 9.63 (s, 1H, for 5H); 8.56 (s, 1H,
2
1
17 H and N-CH CH CH CH CH CH ); 1.77 (d, J ) 7.2 Hz,
3H, 18CH
for 20H); 5.80 (q, J ) 6.8 Hz, 1H, 3 H); 5.42 (m, 17H); 4.46
m, 2H, N-CH CH CH CH CH CH ); 4.37 (q, J ) 7.3 Hz, 1H
for 18H); 3.83 (s, 3H, 12CH ); 3.67 (m, 4H, 8 CH
2
2
2
2
2
3
2
(
2
2
2
2
2
3
3
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH
3
); 1.65-1.10 (m,
1
total for 26H, N-CH CH CH CH CH CH and O-CH CH -
3
2
and O-CH
); 3.57 (s, 3H, 17 CO CH ); 3.33
); 3.20 (s, 3H, 7CH ); 2.68, 2.44 and 2.32 (each m,
2
-
2
2
2
2
2
3
2
2
2
CH CH CH CH CH CH CH CH CH CH ); 0.95 (t, 3H, N-CH -
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
2
3
2
2
2
2
2
2
2
2
2
3
2
(s, 3H, 2CH
3
1
3
CH
2
CH
2
CH
2
CH
2
CH
3
); 0.78 (m, 3H, O-CH
2
CH
2
CH
2
CH
2
CH
2
-
2
CH CH CH CH CH CH CH ); -0.08 and -0.17 (each br s, 1H,
1
3
H, 2 × 17 H and 1 × 17 H); 2.06 (m, J ) 6.7, 2.7 Hz, 3H,
2
2
2
2
2
2
3
1
2
2NH). Mass calcd for C H N O : 847.6. Found: 849.0 (M +
CH
3
); 2.00 (m, 3H, 1 × 17 H and N-CH
2
CH
2
CH
2
CH2-CH
2
-
52 73
5
5
CH
3
); 1.77 (d, J ) 7.2 Hz, 3H, 18CH
3
); 1.69 (t, J ) 7.2 Hz, 3H,
1).
2
8
CH
CH
N-CH
CH CH
Mass calcd for C48
3
); 1.65-1.10 (m, total for 18H, N-CH
and O-CH CH CH CH CH CH CH CH
CH CH CH CH CH ); 0.79 (m, 3H, O-CH
CH CH ); -0.08 and -0.16 (each br s, 1H, 2NH).
: 791.5. Found: 792.5 (M + 1).
2
CH
); 0.96 (t, 3H,
2
CH CH -
2 2 2 2
CH CH CH -
3-(1-(H exyloxy)et h yl)p u r p u r in -18-N-h ep t ylim id e-17-
3
2
2
2
2
2
2
2
3
p r op ion ic Ester (29). Purpurin-18-N-heptylimide 9f (50 mg)
was converted into the related bromo derivative, which when
reacted with 1-hexanol produced the title compound in 70%
yield (40 mg) as a sticky solid after purification on an alumina
2
2
2
2
2
3
2
2
2
2
2
2 3
CH
H
65 5 5
N O
3
-(1-(Non a n yloxy)eth yl)p u r p u r in -18-N-h exylim id e-17-
grade II column, eluting with 25% n-hexanes in CH
2
Cl
2
. UV-
4
3
p r op ion ic Ester (39): Purpurin-18-N-hexylimide 9e (90 mg)
was converted into the related bromo derivative, which when
reacted with 1-nonanol and purified by column chromatogra-
phy produced the title compound in 50% yield (55 mg) as a
sticky solid. UV-vis (in CH
10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H
NMR (400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.77 (s, 1H, for
0H); 9.66 (s, 1H, for 5H); 8.54 (s, 1H, for 20H); 5.78 (q, J )
vis (in CH
2
Cl
× 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz,
3 mg/1 mL CDCl , δ ppm): 9.77 (s, 1H, for 10H); 9.64 (s, 1H,
for 5H); 8.55 (s, 1H, for 20H); 5.79 (q, J ) 6.8 Hz, 1H, 3 H);
5.40 (m, 17H); 4.45 (m, 2H, N-CH CH CH CH CH CH CH );
4.34 (q, J ) 7.3 Hz, 1H for 18H); 3.85 (s, 3H, 12CH ); 3.67 (m,
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81
4
3
5
1
3
1
4
2
Cl
2
): 699 (4.53 × 10 ), 642 (7.35
2
2
2
2
2
2
3
3
4
3
5
1
×
3
1
2
4H, 8 CH
2
and O-CH
2
CH
2
CH
2 2 2 3
CH CH CH
); 3.57 (s, 3H, 17 -
); 2.68, 2.44
3
1
6
CO CH ); 3.32 (s, 3H, 2CH
2
3
3
); 3.21 (s, 3H, 7CH
3
1
1
2
.8 Hz, 1H, 3 H); 5.40 (m, 17H); 4.45 (m, 2H, N-CH
CH CH ); 4.34 (q, J ) 7.3 Hz, 1H for 18H); 3.83 (s, 3H,
2CH ); 3.67 (m, 4H, 8 CH
CH CH
s, 3H, 7CH
2
CH
2
CH
2
-
and 2.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.08 (m, J )
1
2
CH
2
2
3
6.7, 2.7 Hz, 3H, 3 CH
CH CH CH CH CH
(t, J ) 7.2 Hz, 3H, 8 CH
CH
); 0.92 (m, 3H, N-CH
); 0.78 (m, 3H, O-CH CH CH CH
3
); 2.00 (m, 3H, 1 × 17 H and N-CH
2
CH
2
-
1
1
3
2
and O-CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
-
2
2
2
2
3
); 1.74 (d, J ) 7.2 Hz, 3H, 18CH
2
3
); 1.69
2
CH
3
); 3.57 (s, 3H, 17 CO
2
CH
3
); 3.33 (s, 3H, 2CH
3
1
); 3.20
3
); 1.59, 1.49, 1.38 and 1.23 (each m,
2
2
(
1
1
3
); 2.68, 2.44 and 2.32 (each m, 1H, 2 × 17 H and
total for 16H, N-CH
2
2
CH
2
CH
2
CH
2
CH
2
CH
2
3
and O-CH
CH CH CH
CH CH
2
CH
CH
2
-
-
2
1
× 17 H); 2.06 (m, J ) 6.7, 2.7 Hz, 3H, 3 -CH
3
); 2.00 (m, 3H,
CH
CH
2
CH
CH
2
CH2-CH
3
2
2
2
2
2
× 17 H and N-CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
); 1.77 (d, J ) 7.2
2
3
2
2
2
2
2
3
); -0.08
2
Hz, 3H, 18CH
3
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH
CH CH CH CH CH
CH ); 0.95 (t, 3H, N-CH
); 0.78 (m, 3H, O-CH CH CH CH CH
3
); 1.65-1.10
and -0.17 (each br s, 1H, 2NH). Mass calcd for C47
777.5. Found:778.5 (M + 1).
63 5 5
H N O :
(
m, total for 20H, N-CH
2
2
2
2
2
3
and O-CH
2
CH
2
2
2
-
-
-
CH
CH
CH
2
2
2
CH
CH
CH
2
CH
CH
2
CH
2
CH
2
CH
2
3
2
CH
CH
2
CH
CH
3-(1-(Hep tyloxy)eth yl)p u r p u r in -18-N-h ep tylim id e-17-
p r op ion ic Ester (21). Purpurin-18-N-heptylimide 9f (80 mg)
was converted into the related bromo derivative, which when
reacted with 1-heptanol produced the title compound in 70%
yield (65 mg) as a sticky solid after purification on an alumina
2
3
2
2
2
2
2
2
3
); -0.08 and -0.17 (each br s, 1H, 2NH). Mass calcd
for C49
H
67 5 5
N O
: 805.5. Found: 806.3.
3
-(1-(Decyloxy)eth yl)pu r pu r in -18-N-h exylim ide-17-pr o-
p ion c Ester (40). Purpurin-18-N-hexylimide 9e (90 mg) was
converted into the related bromo derivative, which when
reacted with 1-decanol produced the title compound in 55%
yield (60 mg) as a sticky solid after purification on an alumina
grade II column, eluting with 25% n-hexanes in CH
2
Cl
2
. UV-
4
3
vis (in CH
2
Cl
× 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz,
3 mg/1 mL CDCl , δ ppm): 9.77 (s, 1H, for 10H); 9.66 (s, 1H,
for 5H); 8.54 (s, 1H, for 20H); 5.79 (q, J ) 6.8 Hz, 1H, 3 H);
5.40 (m, 17H); 4.45 (m, 2H, N-CH CH CH CH CH CH CH );
4.34 (q, J ) 7.3 Hz, 1H for 18H); 3.85 (s, 3H, 12CH ); 3.67 (m,
); 3.57 (s, 3H,
); 3.21 (s, 3H, 7CH ); 2.68, 2.44
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81
4
3
5
1
3
1
grade II column, eluting with 50% n-hexanes in CH
2
Cl
2
. UV-
4
3
vis (in CH
2
Cl
10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz,
mg/1 mL CDCl , δ ppm): 9.78 (s, 1H, for 10H); 9.65 (s, 1H,
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81
2
2
2
2
2
2
3
4
3
5
1
×
3
1
3
3
4H, 8 CH
2
and O-CH
2 2 2 2 2 2 3
CH CH CH CH CH CH
1
2
for 5H); 8.54 (s, 1H, for 20H); 5.79 (q, J ) 6.8 Hz, 1H, 3 H);
17 CO
2
CH
3
); 3.32 (s, 3H, 2CH
3
1
3
2
5
.42 (m, 17H); 4.45 (m, 2H, N-CH
2
CH
2
CH
2
CH
2
3
2
CH
); 3.67 (m, 4H,
CH CH ); 3.57
);
2
CH
3
); 4.37
and 2.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.08 (m, J )
1
2
(
8
q, J ) 7.3 Hz, 1H for 18H); 3.83 (s, 3H, 12CH
6.7, 2.7 Hz, 3H, 3 CH
CH CH CH CH CH
(t, J ) 7.2 Hz, 3H, 8 CH
CH
CH ); 0.92 (m, 3H, N-CH
); 0.78 (m, 3H, O-CH CH CH CH
3
); 2.00 (m, 3H, 1 × 17 H and N-CH
2
CH
2
-
1
CH
2
and O-CH
2
CH
3
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
3
2
2
2
2
3
); 1.74 (d, J ) 7.2 Hz, 3H, 18CH
2
3
); 1.69
2
(s, 3H, 17 CO
2
CH
); 3.33 (s, 3H, 2CH
3
1
); 3.20 (s, 3H, 7CH
3
3
); 1.59, 1.49, 1.38 and 1.23 (each m,
2
2
.68, 2.44 and 2.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.06
total for 18H, N-CH
2
2
CH
2
CH
2
CH
2
CH2-CH
3
and O-CH
CH CH CH
CH CH CH
2
-
-
1
2
(
m, J ) 6.7, 2.7 Hz, 3H, 3 CH
N-CH CH CH CH CH CH
.69 (t, J ) 7.2 Hz, 3H, 8 CH
N-CH CH CH CH CH CH and O-CH
CH CH CH CH ); 0.95 (t, 3H, N-CH
.78 (m, 3H, O-CH CH CH CH CH
3
); 2.00 (m, 3H, 1 × 17 H and
CH
CH
2
CH
CH
2
CH
CH
2
CH
2
CH
2
3
2
2
2
2
2
2
2
2
2
3
); 1.77 (d, J ) 7.2 Hz, 3H, 18CH
3
);
2
2
3
2
2
2
2
2
2
3
);
2
1
3
); 1.65-1.10 (m, total for 22H,
-0.07 and -0.17 (each br s, 1H, 2NH). Mass calcd for
: 791.5. Found: 793.1 (M + 1).
-(1-(Hexyloxy)eth yl)pu r pu r in -18-N-octylim ide-17-pr o-
2
2
2
2
2
3
2
CH CH CH CH CH
2
2
2
2
2
-
48 65 5 5
C H N O
2
2
2
3
2
2
CH
CH
2
2
CH
CH
2
2
CH
CH
2
2
CH
CH
2
2
CH
CH
3
3
);
);
3
0
-
2
2
2
2
p ion ic Ester (30). Purpurin-18-N-octylimide 9g (100 mg) was
converted into the related bromo derivative, which when
reacted with 1-hexanol produced the title compound in 75%
yield (85 mg) as a sticky solid after purification on an alumina
0.07 and -0.16 (each br s, 1H, 2NH). Mass calcd for
: 819. 5. Found: 821.2 (M + 1).
-(1-(Dod ecyloxy)eth yl)p u r p u r in -18-N-h exylim id e-17-
p r op ion ic Ester (41). Purpurin-18-N-hexylimide 9e (70 mg)
C
50
H
69
N
5
O
5
3
2 2
grade II column, eluted with 33% n-hexanes in CH Cl . UV-

3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1557
4
3
vis (in CH
2
Cl
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81
CH
(s, 3H, 12CH
CH CH ); 3.56 (s, 3H, 17 CO
(s, 3H, 7CH
2
CH
2
CH
2
CH
2 3
CH ); 4.36 (q, J ) 7.4 Hz, 1H for 18H); 3.85
4
3
5
1
1
×
10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz,
3
); 3.67 (m, 4H, 8 CH
2
and O-CH
2 2 2 2
CH CH CH -
2
3
mg/1 mL CDCl
3
, δ ppm): 9.77 (s, 1H, for 10H); 9.66 (s, 1H,
2
3
2
CH
3
); 3.31 (s, 3H, 2CH
3
1
); 3.21
1
for 5H); 8.54 (s, 1H, for 20H); 5.79 (q, J ) 6.8 Hz, 1H, 3 H);
.40 (m, 17H); 4.45 (m, 2H, N-CH CH CH CH CH CH
CH ); 4.34 (q, J ) 7.3 Hz, 1H for 18H); 3.85 (s, 3H, 12CH
3
); 2.67, 2.42 and 2.32 (each m, 1H, 2 × 17 H and
2
1
5
2
2
H
2
2
2
2
2
-
1 × 17 H); 2.06 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
); 1.99 (m, 3H,
2
3
3
);
); 3.57 (s,
); 3.21 (s, 3H, 7CH ); 2.67,
1 × 17 H and N-CH
2
CH
2
CH
3
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
2
CH
3
);
);
1
3
3
2
.67 (m, 4H, 8 CH
H, 17 CO
2
and O-CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
1.76 (d, J ) 7.2 Hz, 3H, 18CH
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH
CH CH CH CH CH
CH CH ); 0.89 (t, 3H, N-
CH ); 0.78 (m, 3H, O-CH
); -0.07 and -0.17 (each br s, 1H, 2N-
: 819.5. Found: 821.1 (M + 1).
-(1-(Decyloxy)eth yl)pu r pu r in -18-N-decylim ide-17-pr o-
3
2
2
CH
3
); 3.32 (s, 3H, 2CH
3
1
3
1.64-1.19 (m, total for 22H, N-CH
2
2
2
2
2
2 2
CH -
2
.42 and 2.31 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.07 (m,
CH
CH
CH
2
CH
CH
CH
2
CH
CH
CH
3
and O-CH
CH CH CH
CH CH
2
CH
CH
2
CH
CH
2
CH
CH
2
2
3
1
2
J ) 6.7, 2.7 Hz, 3H, 3 CH
N-CH CH CH CH CH CH
8CH
3
); 1.99 (m, 3H, 1 × 17 H and
2
2
2
2
2
2
2
2
2
3
2
-
2
2
2
2
2
2
CH
3
); 1.74 (d, J ) 7.2 Hz, 3H,
2
2
2
2
3
2
1
3
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH
3
); 1.65-1.19 (m, total
69 5 5
H). Mass calcd for C50H N O
for 18H, N-CH
2
CH
3
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
CH
CH
3
and O-CH
2
CH
CH
); -0.07
65 5 5
H N O :
2
-
-
3
CH
CH
2
CH
CH
2
CH
2
CH
); 0.91 (m, 3H, N-CH
2
2
CH
2
CH
CH
2
CH
3
2
2
p ion ic Ester (23). Purpurin-18-N-decylimide 7h (100 mg) was
converted into the related bromo derivative, which when
reacted with 1-decanol produced the title compound in 70%
yield (85 mg) as a sticky solid after purification over a alumina
2
3
); 0.79 (m, 3H, O-CH
2
CH
2
CH
2
2
CH
2
and -0.17 (each br s, 1H, 2NH). Mass cald for C48
91.5. Found: 793.0 (M + 1).
-(1 -(Oct yloxy)et h yl)p u r p u r in -18 -N-oct ylim id e-17-
p r op ion ic Ester (22): Purpurin-18-N-octylimide 9g (100 mg)
was converted into the related bromo derivative, which when
reacted with 1-octanol produced the title compound in 70%
yield (83 mg) as a sticky solid after purification on an alumina
7
3
grade II column, eluting with 75% n-hexanes in CH
2
Cl
2
). UV-
4
3
vis (in CH
2
Cl
× 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz,
3 mg/1 mL CDCl , δ ppm): 9.78 (s, 1H, for 10H); 9.66 (s, 1H,
for 5H); 8.55 (s, 1H, for 20H); 5.79 (q, J ) 6.8 Hz, 1H, 3 H);
5.41 (m, 17H); 4.45 (m, 2H, N-CH CH CH CH CH CH CH
CH CH CH ); 4.35 (q, J ) 7.4 Hz, 1H for 18H); 3.85 (s, 3H,
12CH ); 3.67 (m, 4H, 8 CH
CH CH CH CH ); 3.56 (s, 3H, 17 CO
3.21 (s, 3H, 7CH
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81
4
3
5
1
3
1
grade II column, eluting with 33% n-hexanes in CH
2
Cl
2
). UV-
2
2
2
2
2
2
2
-
4
3
vis (in CH
2
Cl
10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400 MHz,
mg/1 mL CDCl , δ ppm): 9.77 (s, 1H, for 10H); 9.66 (s, 1H,
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543 (1.81
2
2
3
4
3
5
1
1
×
3
2
and O-CH
2
CH
2 2 2 2 2
CH CH CH CH -
2
3
3
2
2
2
3
2
CH ); 3.31 (s, 3H, 2CH );
3
3
1
1
for 5H); 8.55 (s, 1H, for 20H); 5.80 (q, J ) 6.8 Hz, 1H, 3 H);
.41 (m, 17H); 4.45 (m, 2H, N-CH CH CH CH CH CH CH
CH
3
); 2.67, 2.42 and 2.32 (each m, 1H, 2 × 17 H
1
3
2
5
2
2
2
2
2
2
2
-
and 1 × 17 H); 2.06 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
); 1.99 (m,
2
3
); 4.34 (q, J ) 7.3 Hz, 1H for 18H); 3.85 (s, 3H, 12CH
3
);
3
);
3
);
3H, 1 × 17 H and N-CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH CH CH -
2
2
2
1
3
3
2
.67 (m, 4H, 8 CH
.57 (s, 3H, 17 CO
2
and O-CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
CH
3
); 1.76 (d, J ) 7.2 Hz, 3H, 18CH
3
3
); 1.69 (t, J ) 7.2 Hz, 3H,
2
2
2
CH ); 3.32 (s, 3H, 2CH
3
3
); 3.21 (s, 3H, 7CH
8 CH ); 1.65-1.09 (m, total for 30H, N-CH
2
CH
CH
2
CH
CH
2
CH
2
CH
2
2
2
2
-
-
-
-
1
2
.67, 2.42 and 2.31 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.07
CH
CH
CH
CH
2
2
2
2
CH
CH
CH
CH
2
CH
2
CH
2
CH
3
and O-CH
2
CH
2
CH
2
CH
2
2
2
CH
CH
CH
2
CH
CH
CH
1
2
(
m, J ) 6.7, 2.7 Hz, 3H, 3 CH
N-CH CH CH CH CH CH CH
8CH
for 22H, N-CH
3
); 1.99 (m, 3H, 1 × 17 H and
3
); 0.88 (t, 3H, N-CH
2
CH
CH
2
CH
CH
2
CH
CH
2
CH
CH
2
CH
CH
2
2
2
2
2
2
2
2
2
3
); 1.74 (d, J ) 7.2 Hz, 3H,
3
3
); 0.80 (m, 3H, O-CH
2
2
2
2
2
2
2
1
3
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH
CH CH CH CH CH CH
CH CH ); 0.91 (m, 3H, N-CH
CH ); 0.78 (m, 3H, O-CH CH CH
3
); 1.66-1.10 (m, total
); -0.07 and -0.17 (each br s, 1H, 2N-H). Mass calcd
2
2
2
2
2
2
2
CH
3
and O-CH
2
CH
CH
CH
2
2
2
-
-
-
for C54
H
77 5 5
N O : 875.6. Found: 876.7 (M + 1).
CH
CH
CH
2
2
2
CH
CH2-CH
CH
2
CH
2
CH
2
2
3
2
CH
CH
2
CH
CH
2
2
3
-(1-(Met h yloxy)et h yl)p u r p u r in -18-N-d od ecylim id e-
2
3
2
2
2
2
1
7-p r op ion ic Ester (42). Purpurin-18-N-dodecylimide 7i (100
3
); -0.07 and -0.17 (each br s, 1H, 2NH). Mass calcd
mg) was converted into the related bromo derivative, which
when reacted with anhydrous methanol produced the title
compound in 75% yield (78 mg) as a sticky solid after
for C50
H
69 5 5
N O
: 819.5. Found: 821.0.
3
-(1-(P r op yloxy)et h yl)p u r p u r in -18-N-d ecylim id e-17-
p r op ion c Ester (44): Purpurin-18-N-decylimide 9h (70 mg)
was converted into the related bromo derivative, which when
reacted with 1-propanol produced the title compound in 80%
yield (60 mg) as a sticky solid after purification over a alumina
purification on an alumina grade II column, eluting with 25%
4
n-hexanes in CH
2
Cl
2
. UV-vis (in CH
2
Cl
2
): 699 (4.53 × 10 ),
3
4
3
642 (7.35 × 10 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28
5
1
× 10 ). H NMR (400 MHz, 3 mg/1 mL CDCl
3
, δ ppm): 9.68
grade II column and eluting with 33% n-hexanes in CH
2
Cl
2
.
and 9.66 (each s, 1H, for 10H and 5H); 8.56 (s, 1H, for 20H);
4
3
1
UV-vis (in CH
2
Cl
1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR (400
MHz, 3 mg/1 mL CDCl , δ ppm): 9.78 (s, 1H, for 10H); 9.66
s, 1H, for 5H); 8.55 (s, 1H, for 20H); 5.80 (q, J ) 6.8 Hz, 1H,
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ), 543
5.75 (q, J ) 6.8 Hz, 1H, 3 H); 5.41 (m, 1H for 17-H); 4.46 (m,
4
3
5
1
(
2H, N-CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2 3
CH ); 4.35
3
(q, J ) 7.4 Hz, 1H for 18H); 3.85 (s, 3H, 12CH
3
); 3.69 (q, J )
1
2
(
3
7.7 Hz, 2H, 8 CH
2
); 3.56 (s, 3H, 17 CO
2
CH
3
); 3.55 (splitting s,
); 2.68, 2.43
1
1
H); 5.40 (m, 17H); 4.46 (m, 2H, N-CH
CH CH CH ); 4.35 (q, J ) 7.4 Hz, 1H for 18H); 3.85 (s,
H, 12CH ); 3.67 (m, 4H, 8 CH
CH ); 3.31 (s, 3H, 2CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
-
3H, 3 OCH
3
); 3.34 (s, 3H, 2CH
3
1
); 3.21 (s, 3H, 7CH
3
2
CH
2
2
2
3
and 2.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.07 (m, J )
1
1
2
3
3
2
3
2
and O-CH
3
1
2
CH
2
CH
3
); 3.56 (s,
); 2.67,
6.7, 2.7 Hz, 3H, 3 CH
CH CH CH CH CH
3H, 18CH
3
); 1.99 (m, 3H, 1 × 17 H and N-CH
2 2
CH -
2
H, 17 CO
2
3
); 3.20 (s, 3H, 7CH
3
2
2
2
2
2
CH
2
CH
2
CH
2
CH
2
CH
3
2
); 1.76 (d, J ) 7.2 Hz,
2
.42 and 2.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.07 (m,
3
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH ); 1.64-1.24 (m,
3
1
2
J ) 6.7, 2.7 Hz, 3H, 3 CH
N-CH CH CH CH CH CH
Hz, 3H, 18CH
m, total for 16H, N-CH
CH CH ); 0.96 (m, 3H, O-CH
CH CH CH CH CH CH CH
0.17 (each br s, 1H, 2NH). Mass calcd for C47
3
); 1.99 (m, 3H, 1 × 17 H and
total for 18H, N-CH
2
CH
); 0.88 (t, 3H, N-CH
CH CH
2
CH2-CH
2
CH
2
CH
2
CH
CH
2
CH
CH
2
CH
CH
2
CH
CH
2
-
-
2
2
2
2
2
2
CH
2
CH
2
CH
2
CH
3
); 1.75 (d, J ) 7.2
CH
CH
2
CH
CH
3
2
CH
2
CH
2
CH
2
2
2
2
2
2
3
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH
3
); 1.64-1.23
2
2
2
3
); -0.10 and -0.17 (each br s, 1H, 2N-H).
: 777.5. Found: 779.2 (M + 1).
-(1-(Hexyloxy)eth yl)p u r p u r in -18-N-d od ecylim id e-17-
(
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
); 0.88 (t,
); -0.07 and
: 777.5.
2
CH
2
CH
3
63 5 5
Mass calcd for C47H N O
and O-CH
2
2
3
2
2 3
CH CH
3
3
H, N-CH
2
2
2
2
2
2
2
2 2 3
CH CH
p r op ion ic Ester (32). Purpurin-18-N-dodecylimide 9i (100
mg) was converted into the related bromo derivative, which
when reacted with 1-hexanol produced the title compound in
70% yield (80 mg) as a sticky solid after purification over a
-
H
63
N
5
O
5
Found: 779.0 (M + 1).
3
-(1-(Hexyloxy)eth yl)pu r pu r in -18-N-decylim ide-17-pr o-
p ion ic Ester (31): Purpurin-18-N-decylimide 9h (70 mg) was
converted into the related bromo derivative, which when
reacted with 1-hexanol produced the title compound in 70%
yield (56 mg) as a sticky solid after purification on an alumina
2
alumina grade II column, eluting with 50% n-hexanes in CH -
4
3
Cl
543 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H NMR
(400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.77 (s, 1H, for 10H);
9.67 (s, 1H, for 5H); 8.55 (s, 1H, for 20H); 5.79 (q, J ) 6.8 Hz,
2
. UV-vis (in CH
2
Cl
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ),
4
3 5 1
3
2
grade II column and eluting with 50% n-hexanes in CH -
4
3
1
Cl
5
(
9
1
2
).UV-vis (in CH
2
Cl
43 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). HNMR
400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.77 (s, 1H, for 10H);
.66 (s, 1H, for 5H); 8.55 (s, 1H, for 20H); 5.80 (q, J ) 6.8 Hz,
2
): 699 (4.53 × 10 ), 642 (7.35 × 10 ),
1H, 3 H); 5.40 (m, 17H); 4.45 (m, 2H, N-CH
CH CH CH CH CH CH CH ); 4.35 (q, J ) 7.4 Hz, 1H for 18H);
3.85 (s, 3H, 12CH ); 3.67 (m, 4H, 8 CH
CH CH CH ); 3.56 (s, 3H, 17 CO
(s, 3H, 7CH
); 2.67, 2.42 and 2.30 (each m, 1H, 2 × 17 H and
2 2 2 2 2
CH CH CH CH -
4
3
5
1
2
2
2
2
2
2
3
1
3
3
2
and O-CH
2
CH
2 2
CH -
2
2
2
3
2
CH
3
); 3.31 (s, 3H, 2CH
3
); 3.20
1
1
H, 3 H); 5.40 (m, 17H); 4.46 (m, 2H, N-CH
2
CH
2
CH
2
CH
2
CH
2
-
3

1
558 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Zheng et al.
2
1
is the singlet oxygen quantum yield (Φr
1
1
CH
× 17 H); 2.07 (m, J ) 6.7, 2.7 Hz, 3H, 3 CH
3
); 1.98 (m, 3H,
CH CH CH CH
); 1.69 (t, J ) 7.2 Hz,
∆
) 0.62), and η is the
2
× 17 H and N-CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
2
2
2
2
-
quenching efficiency given by
2
CH
3
); 1.76 (d, J ) 7.2 Hz, 3H, 18CH
3
3
2
3
H, 8 CH
); 1.65-1.21 (m, total for 26H, N-CH
2
CH
CH
CH
CH
2
2
2
CH
CH
CH
2
2
2
CH
CH
CH
2
2
2
-
-
-
η ) kTΣ[O ]/(k + k [O ])
(2)
2
o
TΣ
2
CH
CH
CH
2
2
2
CH
CH
CH
2
3
2
CH
); 0.88 (t, 3H, N-CH
CH CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
and O-CH
CH CH CH
CH CH
2
2
CH
2
2
2
2
where k
o
is the decay rate constant of the triplet in argon-
2
3
); 0.79 (m, 3H, O-CH
2
2
2
2 2 3
CH CH );
saturated solutions and kTΣ is the bimolecular rate constant
for quenching of the triplet state by oxygen. In our experi-
-
0.08 and -0.18 (each br s, 1H, 2N-H). Mass calcd for
: 847.6. Found: 848.0.
-(1-(Dod ecyloxy)eth yl)p u r p u r in -18-N-d od ecylim id e-
7-p r op ion ic Ester (24). Purpurin-18-N-dodecylimide 9i (100
52 73 5 5
C H N O
ments, all measurements showed that kTΣ . k
o
, making the
3
x
r
ratio η /η close to unity. Thus, relation 1 becomes
1
mg) was converted into the related bromo derivative, which
when reacted with 1-dodecanol produced the title compound
in 60% yield (75 mg) as a sticky solid after purification over
x
x
r
r
kx-r ) Φ A /Φ A
(3)
∆
∆
Measurements of singlet oxygen O
2
(1∆
g
) generated from the
on an alumina grade II column, eluting with 75% n-hexanes
4
standard were made before and after the measurements done
with the samples under investigation, which confirmed that
the instrument response remained constant.
in CH
1
2
Cl
2
. UV-vis (in CH
2
Cl
2
): 699 (4.53 × 10 ), 642 (7.35 ×
3
4
3
5
1
0 ), 543 (1.81 × 10 ), 507 (7.54 × 10 ), 414 (1.28 × 10 ). H
NMR (400 MHz, 3 mg/1 mL CDCl , δ ppm): 9.78 (s, 1H, for
0H); 9.66 (s, 1H, for 5H); 8.55 (s, 1H, for 20H); 5.79 (q, J )
3
1
6
1
.8 Hz, 1H, 3 H); 5.41 (m, 17H); 4.45 (m, 2H, N-CH
CH CH CH CH CH CH CH CH ); 4.35 (q, J ) 7.4 Hz, 1H
for 18H); 3.85 (s, 3H, 12CH ); 3.67 (m, 4H, 8 CH
CH CH CH CH CH CH CH CH CH CH CH ); 3.56 (s, 3H,
72CO
CH ); 3.31 (s, 3H, 2CH ); 3.21 (s, 3H, 7CH ); 2.67, 2.42,
2
CH
2
CH
2
-
Ack n ow led gm en t. The authors are grateful to the
National Institutes of Health (CA 55791) for the finan-
cial support. Partial support by shared resources of the
Roswell Park Cancer Support Grant (P30CA16056) is
also acknowledged.
CH
2
2
2
2
2
2
2
2
3
1
3
2
2
and O-CH -
2
2
2
2
2
2
2
2
2
2
3
1
2
3
3
1
3
2
and 2.32 (each m, 1H, 2 × 17 H and 1 × 17 H); 2.06 (m, J )
1
2
6
.7, 2.7 Hz, 3H, 3 CH
CH CH CH CH CH
H, 18CH
total for 38H, N-H
3
); 1.99 (m, 3H, 1 × 17 H and N-CH
2 2
CH -
2
2
2
2
2
CH
2
CH
2
CH
2
CH
2
CH
3
2
); 1.76 (d, J ) 7.2 Hz,
Refer en ces
3
3
); 1.69 (t, J ) 7.2 Hz, 3H, 8 CH
CH CH CH CH CH CH
CH CH CH CH CH CH
); 0.88 (t, 3H, N-CH CH CH CH CH
CH ); 0.80 (m, 3H, O-CH CH CH CH
CH CH
3
); 1.65-1.09 (m,
(
1) (a) Dougherty, O. J .; Gomer, C.; Henderson, B. W.; J ori, G.;
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2
2
2
2
2
2
2
CH
CH
CH
CH
2
CH
2
CH
CH
CH
2
CH
CH
CH
2
-
2
-
2
-
2
-
CH
CH
CH
CH
3
and O-CH
2
2
2
2
2
2
2
2
CH
CH
2
2
3
2
2
2
2
2
2
2
2
2
CH
CH
2
3
2
2
2
2
2 2 2
CH CH CH
5
17 (b) Pandey, Herman, C. Photodynamic Therapeutics: Shed-
2
2
2
3
); -0.07 and -0.17 (each br s, 1H, 2N-H).
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Mass calcd for C58
85 5 5
H N O
: 931.7. Found: 932.4 (M + 1).
(
Mea su r em en t of Sin glet Oxygen Qu a n t u m Yield s.
Nanosecond laser flash photolysis experiments were performed
using the third harmonic (355 nm) of a Continuum Surelite I
Q-switched Nd:YAG laser that generates pulses of ca. 6 ns
duration. The solutions of the compounds under examination
were contained in 1 × 1 cm cuvette. Singlet oxygen lumines-
cence at 1270 nm was detected at right angles to the laser
beam direction by a germanium photodiode (Applied Detector
Corp. 403HS) cooled to 77 K. Filters were employed to
minimize pick up of scattered laser light and fluorescence. The
output from the detector-amplifier combination was applied
to the 1 MΩ input connector of a LeCroy 9450 digital CRO.
Typically 100 laser shots were averaged together at each of a
series of different laser intensities selected by a rotary polar-
izing attenuator calibrated with a power meter. The time
profiles of the singlet oxygen luminescence observed from such
experiments were a composite of a fast component resulting
from residual scattered laser light and near-infrared fluores-
cence processed through the time constant of the detector
system (ca. 600 ns) and a slower component that arises from
the singlet oxygen luminescence decay. Fitting the slow
3
76-400.
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(
2
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1
time provided a measure of the O
2
( ∆
g
) concentration (L
0
)
prior to the onset of the decay and its subsequent decay
lifetime.
Measurements of L
ties for both the test solutions and for a solution of meso-
tetraphenylporphine (H TPP) in benzene (Φ ) 0.62) having
the same absorbance at 355 nm. These provided values of L
x) and L (r) for the series of laser intensities, where x and r
refer to the test solution and the reference solution, respec-
tively. At low laser intensities, the plots of L (x) versus L (r)
0
were made at a series of laser intensi-
2
∆
0
-
(
0
0
0
were linear. From these plots, the slopes kx-r were extracted
and used to calculate the quantum yield of singlet oxygen of
the unknown solution under the prevailing conditions, accord-
ing to the expression
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x
x
x
r
r
r
kx-r ) (Φ η A )/(Φ η A )
(1)
∆
∆
6
3, 194-205. (b) Bellnier, D. A.; Henderson, B. W.; Pandey, R.
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3
-(1′-Alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides
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J M0005510