In search of novel water soluble forskolin analogues for positive inotropic activity

Article abstract of DOI:10.1016/S0968-0896(98)00124-2

Using the novel lead from hydroxy acetyl substituted forskolin analogues, such as 7β-hydroxyacetyl-7β-deacetyl forskolin or 6β-hydroxyacetyl forskolin, a number of water soluble ω-amino acyl derivatives were synthesized. Two such compounds 6 and 18 showed

Full text of DOI:10.1016/S0968-0896(98)00124-2

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 2075±2083
In Search of Novel Water Soluble Forskolin Analogues for
Positive Inotropic Activity
Bansi Lal,a* Ashok Kumar Gangopadhyay,a Ramesh M. Gidwani,a
Magno Fernandes,a Ramanujam Rajagopalanb, c and Anil Vasantrao Ghateb
aDepartment of Chemistry, Research Centre, Hoechst Marion Roussel Limited, Mulund (W), Mumbai 400 080, India
bDepartment of Pharmacology, Research Centre, Hoechst Marion Roussel Limited, Mulund (W), Mumbai 400 080, India
cDepartment of Pharmacology, Dr. Reddy's Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 138, India
Received 24 March 1998; accepted 16 June 1998
AbstractÐUsing the novel lead from hydroxy acetyl substituted forskolin analogues, such as 7ꢀ-hydroxyacetyl-7ꢀ-
deacetyl forskolin or 6ꢀ-hydroxyacetyl forskolin, a number of water soluble o-amino acyl derivatives were synthesized.
Two such compounds 6 and 18 showed better in vitro activity but failed to show in vivo activity. # 1998 Elsevier
Science Ltd. All rights reserved.
Introduction
derivatives, particularly in 7b-position improved posi-
tive inotropic activity (as shown in Figure 1).
Forskolin was isolated from Coleus forskolii.1 It showed
excellent pharmacological properties such as positive
inotropic, antihypertensive, blood pressure lowering,
intraoccular pressure lowering, adenylate cyclase acti-
vation etc.2
Since we were involved in developing forskolin analo-
gues with better positive inotropic activity preferably
with water solubility, the above information prompted
us to undertake a synthetic project to introduce amino
acyl chain to get water soluble forskolin analogues.
One of the major disadvantages for which forskolin as
such had not been developed subsequently, was its water
insolubility. Subsequent e€ort was made by others to
synthesize water soluble forskolin analogues through
introduction of o-amino acyl chain at 6b- or 7b-posi-
tions. Some of these derivatives showed interesting
pharmacological activity.3a,3b One such compound
NKH-477 is now under clinical development.3b In our
earlier publication4 we have shown that by introducing
a `spacer' in the form of hydroxy acyl chain in 6b- or 7b-
position of deacetyl forskolin or 6b-position of for-
skolin retains the biological activity to large extent
(Fig. 1). Moreover the introduction of acyl chain on
primary ±OH group of the extended chain could be
achieved in a regioselective manner and the resulting
In this paper we would like to report the synthesis and
biological activities of such an e€ort on two forskolin
derivatives such as A and B.
Results and Discussion
Chemistry
Our initial target molecule involved the replacement
of ±COCH3 (in C or D)4 by COCH2NR2 group and solu-
bilize by making appropriate salt. An appropriate inter-
mediate was chosen depending upon the type of
substituent to be introduced. When R=H (glycine resi-
due) or homologous o-amino acyl chain to be intro-
duced, the corresponding protected amino acid was
used. While the preferred approach for the introduction
of secondary amine could be the nucleophilic substitu-
tion reaction on ±COCH2Cl intermediate or Michael
addition across the conjugated double bond (such as
Key words: Forskolin; 2-hydroxy acetyl; o-aminoacyl; positive
inotropic activity.
*Corresponding author. Tel: 0091 22 564 0748; Fax: 0091 22
564 1953; e-mail: bansilal@hoechstres.rpgms.ems.vsnl.net.in
0968-0896/98/$ - see front matter # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00124-2

2076
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2075±2083
Figure 1.
±COCH=CH2). Protecting groups that are acid labile
(under mild condition) being chosen for amino group
protection keeping in mind the presence of ole®n double
bond for which hydrogenolizable groups are unsuitable.
Using this basic approach the synthetic strategy was
adopted.
Further we decided to introduce higher homologue of
amino acyl chain at 7b-OCOCH2OH residue. This had
been done by converting primary OH group of A to
acrylic acid ester followed by Michael addition across
the double bond with di€erent amines. Therefore when
A had reacted with acrylic acid in presence of DCC-
DMAP the reaction had found to be very slow, most of
the starting material remained intact in spite of using
large excess of acrylic acid, DCC and DMAP. A small
amount of product formed in the reaction had found to
be a bad mixture. An alternative approach was adopted
for the synthesis of disubstituted propanoyl analogue.
As a representative example 3,3-diamino propionic acid
was reacted with A in presence of DCC-DMAP to yield
compound 5.
Thus Boc-Gly5 was reacted with 7b-hydroxyacetoxy-
7b-deacetyl forskolin (A) in presence of DCC and
DMAP to give compound 1 (Scheme 1). All attempt to
remove the Boc- group even under mild condition such
as formic acid-anisole6 was unsuccessful leading to a
bad mixture. At this stage we decided to use trityl group
as N-protection. The required intermediate 2 could be
obtained in a similar fashion by reacting 1 with Trit-
Gly7 in presence of DCC-DMAP. In this case also the
removal Trit- group by 85% AcOH8 could not provide
clean reaction. However, when the reaction was carried
out with TFA under dilution (TFA:ether=1:50 v/v), a
clean reaction occurred. The desired product 3 being
isolated from the reaction mixture directly as hydro-
chloride salt since solvent could not be removed in pre-
sence of TFA as it causes complete decomposition of the
product. Introduction of disubstituted glycyl residue on
primary OH group was quite straightforward. Chlor-
oacetic acid was reacted with A in presence of DCC and
DMAP to get chloroacetyl derivative 4 in high yield. It
was then reacted with the desired secondary amine in
dichloromethane at room temperature to yield di-
substituted glycyl analogues 6 and 9±13. However the
yields were not very good (ꢀ 40±60%), because of par-
tial hydrolysis of chloroacetyl group. In some instances
formation of product corresponding to the migration of
the complete chain from 7b to 6b position, which can
easily be seen by the down®eld shift of 6H proton (tri-
A similar series of steps could be performed on 6b-
hydroxy acetyl-7-deacetyl forskolin B to generate com-
pounds 14 to 21 as shown in Scheme 2.
Biological activity
The blood pressure lowering activity of forskolin deri-
vatives was evaluated by intravenous administration to
anesthetized normotensive cats. The positive inotropic
activity of forskolin analogues was tested in sponta-
neously beating isolated guinea pig atrial preparation.
The minimum concentration of the compound required
to obtain force of contraction by 50% (EC50) was
determined and compared with forskolin. The experi-
mental details for the evaluation of biological activity
could be found in earlier publication.9
The results of blood pressure lowering activity and
positive inotropic activity are summarized in Table 1.
From the table it is quite apparent that when 7b-
hydroxy acetyl chain was substituted with o-amino acyl
chain the positive inotropic activity increased in most of
the cases viz. 3, 5, 6, 8, 11 and 12 with EC50 values of
0.1, 0.3, 0.03, 0.55, 0.18 and 0.1 mg/ml respectively when
compared with hydroxy acetyl derivative A. All these
1
plet) and up®eld shift of 7H doublet in H NMR. Dii-
sopropyl amine and trimethoxy aniline failed to react at
room temperature. However when 4 was reacted with
diisopropyl amine at 45 ꢁC and trimethoxy aniline at
70±80 ꢁC desired compounds 7 and 8 could be formed in
40% and 20% yields respectively.

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2075±2083
2077
compounds were found to be highly water soluble. The
most potent compound in the series was found to be 6
which was 1.5 times less active than forskolin which had
EC50 of 0.02 mg/ml. While the similar substitutions on
6b-hydroxyacetyl group (B) were found to be less e€ec-
tive, except in one compound 18 (EC50=0.04 mg/ml), all
the compounds were found to be inactive. Considering
some hypotensive e€ect showed in anesthetized cat,
lower doses were tested for positive inotropic activity
(without causing signi®cant fall in blood pressure) in
anesthetized dog. Compound 6 (in vitro EC50=0.03 mg/
ml) in an iv. infusion of 0.5 mg/kg/min. could increase
cardiac force of contraction only by 20%, while com-
pound 18 (in vitro EC50=0.04 mg/ml) was inactive after
1 mg/kg/min. iv. infusion. All these data suggests a rapid
metabolic degradation of these compounds. One such
possibility could be the hydrolysis of amino acyl chain
from the primary OH group.
Conclusion
In our attempt to develop water soluble forskolin ana-
logues with positive inotropic activity, the modi®cation
under current study resulted two water soluble com-
pounds with good in vitro activity but failed to provide
desired result in vivo.
Scheme 1. 1. DCC, DMAP, EtOAc or (EtOAc+DMF) 2. TFA, ether. 3. HCl, ether. 4. R1R2NH, CH2Cl2, r.t./45 ꢁC (for 7)/70±80 ꢁC
(for 8).

2078
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2075±2083
Experimental
compounds. Vaniline-50% orthophosphoric acid or
anisaldehyde-H2SO4 spray reagent were used and
heated the plates at 110 ꢁC for visualization. All com-
pounds were homogeneous on TLC and gave proper
spectral characteristics.
General procedures
Melting points were determined with a Ko¯er hot stage
apparatus and are uncorrected. IR spectra were deter-
mined with a Perkin±Elmer 157 Spectrophotometer as
KBr ®lm unless otherwise mentioned and the values
were expressed in cm 1. 1H NMR spectra were recorded
in CDCl3 unless otherwise mentioned on a JEOL FT-90
Spectrometer with TMS as internal standard and cou-
pling constant values are expressed in Hz. (Protons at
positions 2 & 3 of ring A in Forskolin are buried under
methyl signals, hence have not been mentioned sepa-
rately). Petroleum ether refers to the fraction of b.p. 60±
80 ꢁC. For ¯ash column chromatography silica gel (®ner
than 0.08 mm particle size) was used. Precoated (silica
gel 60 F254) TLC plates were used for checking purity of
8,13-Epoxy-7ꢀ-(2-tertiarybutyloxycarbonylaminomethyl-
carbonyloxy)acetyloxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-
11-one (1). To a solution of compound A (0.43 g;
1 mmol) and DCC (0.247 g; 1.2 mmol) in EtOAc
(15 mL), a solution of Boc-Gly (0.192 g; 1.1 mmol) in
EtOAc (5 mL) was added under stirring at room tem-
perature, followed by DMAP (0.12 g; 1 mmol). The
reaction mixture was stirred at room temperature for
3 h. The DCU was ®ltered o€ and the ®ltrate was
washed with aqueous NaHCO3 followed by brine. The
EtOAc layer was dried over anhydrous Na2SO4. The
Scheme 2. 1. DCC, DMAP, EtOAc (or EtOAc+DMF) 2. TFA, ether. 3. HCl, ether. 4.
, CH2Cl2, r.t.

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2075±2083
2079
Table 1. Biological activity of Forskolin derivatives
Compound EC50(GP atrium) BP lowering activity (cat)
7ꢀ - (Aminomethylcarbonyloxy)acetyloxy - 8, 13 - epoxy-
1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one, hydrochloride
*
(3). Compound 2 (0.1 g; 0.14 mmol) was dissolved in
ether (10 mL) and TFA (0.2 mL) was added. The clear
solution was kept at room temperature. When most of
the starting material disappeared (nearly 1 h), ethereal
HCl was added dropwise till no further precipitation
occurred. The white solid was ®ltered o€ and washed
with dry ether several times. The solid was dried in a
vacuum pump for 2 h. The white solid was recrystallized
from MeOH±dry ether. Yield 0.052 g (68.9%); IR: 3360
No.
(mg/mL)
Dose (iv) Fall in BP Duration
(mg/kg) (mm of Hg) (in min.)
1
NA
0.1
0.3
1.0
0.1
Ð
40
120
40
60
>70
120
Ð
3
5
0.3
6
0.03
1.0
Ð
7
0.1
3.0
1.0
Ð
20
>210
>120
60
1
(br), 2950 (br), 1765, 1760, 1727; H NMR (CD3OD):
8
0.55
NA
NA
0.5
100
60
1.0, 1.25, 1.32, 1.43, 1.70 (5Âs, 15H, 5ÂCH3), 2.1 (d,
1H, J=3.04, 5H), 2.35 (d, 1H, Jgem=16.2, 12bH), 3.2 (d,
1H, Jgem=16.2, 12aH), 3.94 (s, 2H, COCH2N), 4.35±
4.46 (m, 2H, 1H & 6H), 4.85 (dd, 1H, Jcis=10.53,
9
10
Ð
Ð
11
1.0
0.3
3.0
5.0
Ð
60
30
12
0.1
80
60
13
>1.0
>10.0
0.58
0.04
Ð
80
100
>90
Ð
Jgem=1.62, 15Hcis), 4.90 (s, 2H, COCH2O), 5.06 (dd,
15
80
1H, Jtrans=17.21, Jgem=1.62, 15Htrans), 5.95 (d, 1H,
J=4.56, 7H), 6.02 (dd, 1H, Jtrans=17.21, Jcis=10.53,
14H). Anal. calcd for C24H38O9NCl, H2O: C, 53.57; H,
7.49; N, 2.60; Cl, 6.59; found: C, 53.63; H, 7.59; N, 2.58;
Cl, 6.44%.
17
Ð
18
1.0
NA
3.0
Ð
40
30
19
20
Ð
20
Ð
30
Ð
21
1.0
Forskolin
0.02
0.1
63.7‹5.5 55.0‹3.9
7ꢀ-(Chloroacetyloxy)acetyloxy-8,13-epoxy-1ꢁ,6ꢀ,9ꢁ-tri-
A (4.4 g;
NA=Not active; -=Not done *No signi®cant activity below
the dose mentioned.
hydroxylabd-14-en-11-one (4). Compound
10.33 mmol) was stirred at room temperature with
chloroacetic acid (1.04 g; 11 mmol), DCC (2.47 g;
12 mmol) and DMAP (1.34 g; 10.98 mmol) in EtOAc
(60 mL) for 16 h. The DCU was ®ltered o€ and the ®l-
trate was washed with 1N aq. NaHCO3 followed by
brine. The EtOAc layer was dried over anhydrous
Na2SO4. The solvent was evaporated and the crude
product was puri®ed by ¯ash chromatography with
10% CH3CN±CHCl3. Yield 4 g. (77.1%); m.p., 168±
70 ꢁC (EtOAc±light petroleum); IR: 3450, 2950, 1790,
solvent was evaporated. The residue was puri®ed by
¯ash chromatography with 30% EtOAc±light petro-
leum. Yield, 0.43 g (73.7%) as amorphous powder; IR:
3460 (br), 3000, 2960, 1765 (br), 1725 (br); 1H NMR:
1.02, 1.26, 1.34, 1.71 (4Âs, 12H, 4ÂCH3), 1.46 [s, 12H,
CH3+C(CH3)3], 2.14 (d, 1H, J=2.53, 5H), 2.44 (d, 1H,
Jgem=16.71, 12bH), 3.16 (d, 1H, Jgem=16.71, 12aH),
3.85±4.02 (m, 2H, COCH2NH), 4.44 (t, 1H, J=3.04,
6H), 4.54 (br, 1H, 1H), 4.72 (s, 2H, COCH2O), 4.93 (dd,
1H, Jcis=10.13, Jgem=1.6, 15Hcis), 5.21 (dd, 1H,
1
1775, 1715, 1705; H NMR: 1.06, 1.30, 1.37, 1.46, 1.71
(5Âs, 15H, 5ÂCH3), 2.19 (d, 1H, J=3.04, 5H), 2.45 (d,
1H, Jgem=17.21, 12bH), 3.19 (d, 1H, Jgem=17.21,
12aH), 4.06 (s, 2H, CH2Cl), 4.56 (m, 2H, 1H & 6H),
4.80 (s, 2H, COCH2O), 4.94 (dd, 1H, Jcis=11.13,
Jtrans=17.21, Jgem=1.6, 15Htrans), 5.45 (d, 1H, J=4.05,
7H), 5.91 (dd, 1H, Jtrans=17.21, Jcis=10.13, 14H). Anal.
calcd for C29H45O11N : C, 59.68; H, 7.77; N, 2.40;
found: C, 59.88; H, 7.92; N, 2.31%.
J
J
gem=2.03, 15Hcis), 5.21 (dd, 1H, Jtrans=17.21,
gem=2.03, 15Htrans), 5.48 (d, 1H, J=4.05, 7H), 5.96
8,13-Epoxy-1ꢁ,6ꢀ,9ꢁ-trihydroxy-7ꢀ-(tritylaminomethyl-
carbonyloxy)acetyloxylabd-14-en-11-one (2). The com-
pound A was treated with Trit-Gly by the same method.
The pure product was amorphous solid. Yield, 82%; IR:
(dd, 1H, Jtrans=17.21, Jcis=11.13, 14H). Anal. calcd for
C24H35O9Cl : C, 57.31; H, 7.01; Cl, 7.05; found: C,
57.29; H, 7.23; Cl, 7.20%.
1
3542 (br), 2975, 2945, 1757, 1725; H NMR: 1.03, 1.24,
7ꢀ-[3-(Dimethylamino)propanoyloxy]acetyloxy-8,13-epoxy-
1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (5). Compound
A (0.426 g; 1 mmol) and DCC (0.21 g; 1.02 mmol) were
dissolved in EtOAc (5 mL) and DMF (2 mL). To the
clear solution 3-dimethylaminopropionic acid hydro-
chloride (0.153 g; 1 mmol) was added followed by
DMAP (0.185 g; 1.5 mmol). The reaction mixture was
stirred at room temperature for 16 h. After usual work
up (see exptl for 1). The crude product was puri®ed by
¯ash chromatography with 20% CH3CN±CHCl3
1.31, 1.43, 1.64 (5Âs, 15H, 5ÂCH3), 2.16 (br, 1H, 5H),
2.41 (d, 1H, Jgem=17.2, 12bH), 3.18 (d, 1H, Jgem=17.2,
12aH), 3.34 (br, 2H, CH2NH), 4.40±4.60 (m, 2H, 1H &
6H), 4.60 (br s, 2H, COCH2O), 4.90 (dd, 1H, Jcis=10.6,
Jgem=2.0, 15Hcis), 5.19 (dd, 1H, Jtrans=17.2, Jgem=2.0,
15Htrans), 5.43 (d, 1H, J=3.04, 7H), 5.92 (dd, 1H,
Jtrans=17.2, Jcis=10.6, 14H), 7.2±7.5 (m, 15H,
15ÂPhH). Anal. calcd for C42H51O9N: C, 71.15; H,
7.08; N, 1.93; found: C, 70.98; H, 7.04; N, 1.89%.

2080
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2075±2083
followed by 10% MeOH±CHCl3. The pure material was
converted into hydrochloride salt in EtOAc and HCl±
dry ether. Yield 56%; m.p., 214±15 ꢁC (MeOH-dry
ether); IR: 3400±3300 (br), 2950 (br), 1775, 1750 (br),
1720; 1H NMR (CDCl3+CD3OD): 1.03, 1.27, 1.36,
1.43, 1.71 (5Âs, 15H, 5ÂCH3), 2.14 (d, 1H, J=3.04,
5H), 2.39 (d, 1H, Jgem=17.21, 12bH), 2.86, 2.89 [2Âs,
6H, N(CH3)2], 2.93±3.17 (br, 3H, CH2CH2N & 12aH),
3.37 (t, 2H, J=6.08, COCH2CH2), 4.49 (br, 2H, 1H &
6H), 4.70, 4.91 (2Âd, 2H, Jgem=15.2, COCH2O), 4.91
(dd, 1H, Jcis=11.14, Jgem=1.5, 15Hcis), 5.16 (dd, 1H,
Jgem=17.21, 12bH), 3.18 (d, 1H, Jgem=17.21, 12aH),
3.99 (m, 4H, 2ÂCHMe2+COCH2NPri2.HCl), 4.43±
4.63 (br, 2H, 1H & 6H), 4.83 (s, 2H, COCH2O), 4.89
(dd, 1H, Jcis=10.13, Jgem=1.63, 15Hcis), 5.19 (dd, 1H,
Jtrans=16.21, Jgem=1.63, 15Htrans), 5.51 (d, 1H, J=4.05,
7H), 5.94 (dd, 1H, Jtrans=16.21, Jcis=10.13, 14H). Anal.
calcd for C30H50O9NCl, 1.5H2O: C, 57.08; H, 8.46; N,
2.22; Cl, 5.62; found: C, 56.97; H, 8.44; N, 2.01; Cl,
5.53%.
8,13-Epoxy-1ꢁ,6ꢀ,9ꢁ-trihydroxy-7ꢀ-[(3,4,5-trimethoxy-
anilino)methylcarbonyloxy]acetyloxylabd-14-en-11-one (8).
A solution of 4 (0.25 g; 0.5 mmol) and 3,4,5-trimethoxy-
aniline (0.18 mL) in toluene (3 mL) was heated at 70±
80 ꢁC for 16 h. The solvent was removed and the residue
was puri®ed by ¯ash chromatography with 10%
CH3CN±CHCl3. Yield, 0.06 g (20%); m.p., 108±09 ꢁC
(EtOAc±light petroleum); IR; 3440 (br), 2950 (br), 1765,
Jtrans=17.21, Jgem=1.5, 15Htrans), 5.41 (d, 1H, J=4.05,
7H), 6.00 (dd, 1H, Jtrans=17.21, Jcis=11.14, 14H). Anal.
calcd for C27H44O9NCl, 2H2O: C, 54.22; H, 8.08; N, 2.34;
Cl, 5.93; found: C, 54.03; H, 8.24; N, 2.32; Cl, 5.69%.
7ꢀ-(Diethylaminomethylcarbonyloxy)acetyloxy-8,13-epoxy-
1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one,
hydrochloride
(6). To solution of (3.96 g; 7.88 mmol) in
1
a
4
1760, 1725; H NMR: 1.03, 1.24, 1.34, 1.41, 1.67 (5Âs,
CH2Cl2 (40 mL), diethyl amine (4 mL) was added and
the clear solution was kept at room temperature for
14 h. The reaction mixture was evaporated to dryness
and the residue was puri®ed by ¯ash chromatography
with 10% CH3CN±CHCl3 (to remove unreacted 4 and
hydrolyzed product A followed by 20% CH3CN±
CHCl3. The fraction containing the required compound
was evaporated and redissolved in EtOAc. To the clear
solution HCl in dry ether was added. The mixture was
evaporated to small volume and excess dry ether was
added. The white precipitate was collected and dried. It
was recrystallized from dry MeOH±dry ether. Yield, 2 g
(44%); m.p., 140±42 ꢁC; IR: 3380 (br), 2960 (br), 1765
15H, 5ÂCH3), 2.19 (d, 1H, J=3.04, 5H), 2.44 (d, 1H,
Jgem=17.21, 12bH), 3.19 (d, 1H, Jgem=17.21, 12aH),
3.74 (s, 3H, OCH3), 3.81 (s, 6H, 2ÂOCH3), 4.03 (s 2H,
COCH2N), 4.54 (br, 2H, 1H & 6H), 4.79 (s, 2H,
COCH2O), 4.93 (dd, 1H, Jcis=11.14, Jgem=1.62,
15Hcis), 5.19 (dd, 1H, Jtrans=17.21, Jgem=1.62,
15Htrans), 5.47 (d, 1H, J=4.05, 7H), 5.86 (s, 2H, ArH),
5.96 (dd, 1H, Jtrans=17.21, Jcis=11.14, 14H). Anal.
calcd for C33H47O12N, H2O: C, 59.35; H, 7.39; N, 2.09 ;
found: C, 59.54 H, 7.22; N, 2.18%.
Compounds 9±13 were prepared from 4 with the use of
appropriate amine by the method as described for the
synthesis of compound 6.
1
(br), 1728; H NMR: 1.03, 1.26, 1.34, 1.43, 1.69 (5Âs,
15H, 5ÂCH3), 1.47 (t, 6H, J=6.58, 2ÂCH2CH3), 2.16
(d, 1H, J=3.04, 5H), 2.41 (d, 1H, Jgem=17.21, 12bH),
3.19 (d, 1H, Jgem=17.21, 12aH), 3.26±3.47 (m, 4H,
2ÂCH3CH2N.HCl), 3.99 (s, 2H, COCH2NEt2), 4.37±
4.60 (br, 2H, 1H & 6H), 4.84 (s, 2H, COCH2O), 4.87
(dd, 1H, Jcis=10.13, Jgem=2.03, 15Hcis), 5.16 (dd, 1H,
Jtrans=17.21, Jgem=2.03, 15Htrans), 5.50 (d, 1H, J=4.05,
7H), 5.90 (dd, 1H, Jtrans=17.21, Jcis=10.13, 14H). Anal.
calcd for C28H46O9NCl, 1.5H2O: C, 55.76; H, 8.19; N,
2.32; Cl, 5.88; found: C, 55.98; H, 8.25; N, 2.23; Cl,
6.18%.
8, 13-Epoxy-7ꢀ-[(homopiperidino)methylcarbonyloxy]-
acetyloxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one
(9).
The crude product was puri®ed by ¯ash chromato-
graphy with 20% CH3CN±CHCl3. Yield, 30%, as
hydrochloride salt; m.p., 146±48 ꢁC; IR; 3400 (br), 2960
(br), 1765 (br), 1728; 1H NMR: 1.04, 1.27, 1.34, 1.44,
1.71 (5Âs, 15H, 5ÂCH3), 1.74±2.31 [m, 8H, 4ÂCH2 (30,
40, 50 & 60)], 2.14 (d, 1H, J=3.04, 5H), 2.43 (d, 1H,
J
gem=17.21, 12bH), 3.19 (d, 1H, Jgem=17.21, 12aH),
3.43 [br, 4H, 2ÂCH2 (20 & 70)], 4.04 (br 2H, COCH2N),
4.56 (br, 2H, 1H & 6H), 4.86 (br, 2H, COCH2O), 4.91
(dd, 1H, Jcis=11.14, Jgem=1.82, 15Hcis), 5.21 (dd, 1H,
7ꢀ-(Diisopropylaminomethylcarbonyloxy)acetyloxy-8,13-
epoxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one,
hydro-
Jtrans=17.21, Jgem=1.82, 15Htrans), 5.51 (d, 1H, J=4.05,
chloride (7). The compound 4 (0.25 g; 0.5 mmol) was
heated with diisopropyl amine (2 mL) at 45 ꢁC for 3 h.
Diisopropyl amine was removed under reduced pressure
and the residue was puri®ed by ¯ash chromatography as
described for 6. Yield, 0.121 g (40%); m.p., 148±50 ꢁC
(MeOH-dry ether); IR: 3410 (br), 2990 (br), 1770 (br),
1730; 1H NMR: 1.03, 1.30, 1.34, 1.43, (4Âs, 12H,
4ÂCH3), 1.49±1.63 [br m, 12H, 2ÂCH(CH3)2], 1.70 (s,
3H, CH3), 2.14 (d, 1H, J=2.53, 5H), 2.44 (d, 1H,
7H), 5.94 (dd, 1H, Jtrans=17.21, Jcis=11.14, 14H). Anal.
calcd for C30H48O9NCl, 1.5 H2O: C, 58.76; H, 8.39; N,
2.28; Cl, 5.78 ; found: C, 58.56 H, 8.12; N, 2.27; Cl,
5.39%.
7ꢀ-(2,6-Dimethylmorpholinomethylcarbonyloxy)acetyloxy-
8,13-epoxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (10).
Yield, 0.094 g (30.5%), as hydrochloride salt; m.p.,
ꢁ
1
158±60 C; IR: 3400 (br), 2950 (br), 1762 (br), 1723; H

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2075±2083
2081
NMR: 1.05 (s, 3H, CH3), 1.23, 1.30 (2Âd, 6H, J=6.38,
2ÂCHCH3), 1.26 (s, 6H, 2ÂCH3), 1.43, 1.69 (2Âs, 6H,
2ÂCH3), 2.27 (d, 1H, J=2.03, 5H), 2.41 (d, 1H,
Jgem=17.21, 12bH), 2.57±2.91 [m, 4H, 2ÂCH2 (30 & 50)],
CH3), 1.20 (t, 3H, J=7.08, OCH2CH3), 1.30, 1.37, 1.46,
1.71 (4Âs, 12H, 4ÂCH3), 2.14 (d, 1H, J=3.04, 5H), 2.42
(d, 1H, Jgem=17.21, 12bH), 2.80 (br, triplet after D2O
exchange, 4H, J=6.08, 20-CH2, 60-CH2), 3.20 (d, 1H,
3.18 (d, 1H,
J
gem=17.21, 12aH), 3.41 (m, 2H,
Jgem=17.21, 12aH), 3.30 (br, t after D2O exchange, 4H,
2ÂCHCH3), 3.84 (m, singlet after D2O exchange, 2H,
COCH2N), 4.37±4.58 (br, 2H, 1H & 6H), 4.81 (s, 2H,
COCH2O), 4.87 (dd, 1H, Jcis=10.13, Jgem=1.6, 15Hcis),
5.17 (dd, 1H, Jtrans=17.21, Jgem=1.6, 15Htrans), 5.48 (d,
1H, J=4.05, 7H), 5.89 (dd, 1H, Jtrans=17.21,
J=6.08, 30-CH2 & 50-CH2), 3.91 (br, triplet after D2O
exchange, 2H, COCH2N), 4.14 (quartet, 2H, J=7.08,
CH2CH3), 4.57 (br, 2H, 1H & 6H), 4.86 (s, 2H,
COCH2O), 4.91 (dd, 1H, Jcis=11.14, Jgem=1.62,
15Hcis), 5.18 (dd, 1H, Jtrans=17.21, Jgem=1.62,
15Htrans), 5.50 (d, 1H, J=4.05, 7H), 5.95 (dd, 1H,
Jcis=10.13, 14H). Anal. calcd for C30H48O10NCl: C,
58.29; H, 7.83; N, 2.27; Cl, 5.74; found: C, 58.05; H,
7.92; N, 2.21; Cl, 5.90%.
Jtrans=17.21, Jcis=11.14, 14H). Anal. calcd for
C31H49O11N2Cl: C, 54.82; H, 7.57; N, 4.12; Cl, 5.21;
found: C, 55.01; H, 7.65; N, 4.12; Cl, 5.92%.
8,13-Epoxy-7ꢀ-[(4-phenylpiperidino)methylcarbonyloxy]-
acetyloxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (11).
The crude product was puri®ed by ¯ash chromatog-
raphy with 10% CH3CN±CHCl3. Yield, 33%; m.p., 99±
101 ꢁC (EtOAc±light petroleum); IR: 3445 (br), 3150
(br), 2970 (br), 1775 (br), 1725; 1H NMR: 1.03, 1.27,
1.36, 1.43, 1.70 (5Âs, 15H, 5ÂCH3), 1.86, 2.20 (2Âm,
5H, 30-CH2, 50-CH2+5H), 2.44 (d, 1H, Jgem=17.21,
12bH), 2.79 (m, 1H, 40-CH), 3.07, 3.17 (2Âm, 5H, 20-
CH2, 60-CH2 & 12aH), 3.39 (s, 2H, COCH2N), 4.43±
4.60 (br, 2H, 1H & 6H), 4.74 (s, 2H, COCH2O), 4.93
(dd, 1H, Jcis=10.63, Jgem=2.03, 15Hcis), 5.20 (dd, 1H,
8,13-Epoxy-1ꢁ,7ꢀ,9ꢁ-trihydroxy-6ꢀ-(tritylaminomethyl-
carbonyloxy)acetyloxylabd-14-en-11-one (14). Compound
B was treated with Trit-Gly by DCC-DMAP method
(see experimental for compound 1) The crude product
was puri®ed by ¯ash chromatography with 15%
EtOAc±light petroleum. Yield, 75%; white amorphous
powder; IR: 3450 (br), 2940 (br), 1755 (br), 1720; 1H
NMR: 0.92, 1.04, 1.24, 1.38, 1.45 (5Âs, 15H, 5ÂCH3),
2.31(d, 1H, J=3.04, 5H), 2.46 (d, 1H, Jgem=17.21,
12bH), 3.16 (d, 1H, Jgem=17.21, 12aH), 3.18 (s, 2H,
COCH2N), 4.23 (br, doublet after D2O, 1H, J=4.23,
7H), 4.56 (br, 3H, COCH2O & 1H), 4.93 (dd, 1H,
Jtrans=17.21, Jgem=2.03, 15Htrans), 5.48 (d, 1H, J=4.56,
7H), 5.94 (dd, 1H, Jtrans=17.21, Jcis=10.63, 14H), 7.21
(br 5H, 5ÂPh-H). Anal. calcd for C35H49O9N: C, 66.96;
H, 7.86; N, 2.23; found: C, 67.23; H, 8.10; N, 2.39%.
J
J
cis=10.13, Jgem=1.52, 15Hcis), 5.11 (dd, 1H,
trans=16.7, Jgem=1.52, 15Htrans), 5.86 (t, 1H, J=2.33,
6H), 6.05 (dd, 1H, Jtrans=16.7, Jcis=10.13, 14H), 7.07±
7.53 (m, 15H, 15ÂPhH). Anal. calcd for C43H51O9N: C,
71.15; H, 7.08; N, 1.93; found: C, 71.32; H, 7.19; N,
1.87%.
8,13-Epoxy-7ꢀ-[(4-methylpiperazino)methylcarbonyloxy]-
acetyloxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (12).
The crude product was puri®ed by ¯ash chromatog-
raphy with 20% CH3CN±CHCl3 followed by 10%
MeOH±CHCl3. Yield, 51% as free base; m.p., 95±97 ꢁC
(EtOAc±light petroleum); IR: 3550 (br), 3220 (br), 2970
(br), 1775 (br), 1725; 1H NMR: 1.04, 1.26, 1.34, 1.43,
1.70 (5Âs, 15H, 5ÂCH3), 2.17 (d, 1H, J=3.04, 5H), 2.29
(s, 3H, NCH3), 2.44 (d, 1H, Jgem=17.21, 12bH), 2.56,
2.63 (2Âm, 8H, 20-CH2, 30-CH2, 50-CH2 & 60-CH2), 3.19
(d, 1H, Jgem=17.21, 12aH), 3.33 (s, 2H, COCH2N),
4.40±4.57 (br, 2H, 1H & 6H), 4.74 (s, 2H, COCH2O),
4.91 (dd, 1H, Jcis=11.13, Jgem=1.82, 15Hcis), 5.19 (dd,
1H, Jtrans=17.21, Jgem=1.82, 15Htrans), 5.48 (d, 1H,
J=4.05, 7H), 5.95 (dd, 1H, Jtrans=17.21, Jcis=11.13,
14H). Anal. calcd for C29H46O9N2: C, 61.46; H, 8.18; N,
4.94; found: C, 61.28; H, 8.39; N, 4.99%.
8,13-Epoxy-6ꢀ-(aminomethylcarbonyloxy)acetyloxy-1ꢁ,
7ꢀ,9ꢁ-trihydroxylabd-14-en-11-one, hydrochloride (15).
This compound was obtained by deprotecting trityl
group from 14 (for details see experimental for 3). Yield,
55%; m.p., 165±67 ꢁC (MeOH±dry ether); IR: 3425 (br),
2925 (br), 1758 (br), 1715; 1H NMR (CD3OD):1.01,
1.03, 1.37, 1.41, 1.53 (5Âs, 15H, 5ÂCH3), 2.36 (d, 1H,
J=3.04, 5H), 2.35, 3.23 (2Âd, 2H, Jgem=16.2, 12bH &
12aH), 3.91 (s, 2H, COCH2N), 4.22 (d, 1H, J=5.06,
7H), 4.46 (br, 1H, 1H), 4.81 (s, 2H, COCH2O), 4.84 (dd,
1H, Jcis=10.33, Jgem=1.5, 15Hcis), 5.09 (dd, 1H,
Jtrans=17.21, Jgem=1.5, 15Htrans), 5.80 (dd, 1H, J=3.04,
5.06, 6H), 6.11 (dd, 1H, Jtrans=17.21, Jcis=10.33, 14H).
Anal. calcd for C24H38O9NCl, H2O: C, 53.57; H, 7.49; N,
2.60; Cl, 6.59; found: C, 53.85; H, 7.49; N, 2.25; Cl, 6.58%.
8,13-Epoxy-7ꢀ-[(4-carbethoxypiperazino)methylcarbonyl-
oxy]acetyloxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (13).
The crude product was puri®ed by ¯ash chromato-
graphy with 18% CH3CN±CHCl3. Hydrochloride salt
was prepared from EtOAc±HCl in dry ether. Yield,
28.4%; m.p., 157±58 ꢁC (MeOH±dry ether); IR: 3420
6ꢀ-(Chloroacetyloxy)acetyloxy-8,13-epoxy-1ꢁ,7ꢀ,9ꢁ-tri-
hydroxylabd-14-en-11-one (16). This compound was
prepared by the same method as described for the pre-
paration of 4 (Scheme 1). The crude product was pur-
i®ed by ¯ash chromatography with 8% CH3CN±CHCl3.
1
1
(br), 2950 (br), 1765 (br), 1725; H NMR: 1.04 (s, 3H,
Yield, 40%; H NMR: 1.0, 1.09, 1.39, 1.41, 1.59 (5Âs,

2082
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2075±2083
15H, 5ÂCH3), 2.37 (d, 1H, J=3.04, 5H), 2.49 (d, 2H,
Jgem=17.21, 12bH), 3.20 (d, 1H, Jgem=17.21, 12aH),
4.16 (s, 2H, COCH2Cl), 4.30 (d, 1H, J=4.56, 7H), 4.64
(br, 1H, 1H), 4.74 (s, 2H, COCH2O), 4.97 (dd, 1H,
converted into hydrochloride salt from dry EtOAc±dry
HCl and crystallized from MeOH±dry ether. Yield,
31%; m.p., 155±56 ꢁC ; IR: 3420±3250 (br), 2970 (br),
1760 (br), 1720; 1H NMR: 1.0, 1.07, 1.39, 1.40, 1.57
(5Âs, 15H, 5ÂCH3), 1.91±2.14 (m, 4H, 30-CH2, & 50-
CH2), 2.37 (br, 1H, 5H), 2.47 (d, 1H, Jgem=16.2, 12bH),
2.61 (m, 1H, 40-CH), 2.71±3.64 (2Âm, 4H, 20-CH2 & 60-
CH2), 3.21 (d, 1H, Jgem=16.2, 12aH); 4.06 (m, 2H,
COCH2N), 4.32 (d, 1H, J=5.06, 7H), 4.66 (br, 1H, 1H),
4.73 (br, s after D2O exchange, 2H, COCH2O), 4.96 (dd,
1H, Jcis=11.14, Jgem=1.52, 15Hcis), 5.15 (dd, 1H,
J
J
cis=10.53, Jgem=1.82, 15Hcis), 5.16 (dd, 1H,
trans=17.21, Jgem=1.82, 15Htrans), 5.94 (dd, 1H,
J=4.05, 3.04, 6H), 6.11 (dd, 1H, Jtrans=17.21,
cis=10.53, 14H). Anal. calcd for C24H35O9Cl: C, 57.31;
H, 7.01; Cl, 7.05; found: C, 57.25; H, 7.08; Cl, 7.25%.
J
The compound 16 was treated with the required amine
in dichloromethane for 16 h as described for the synth-
esis of compound 6 to generate 17 to 20.
Jtrans=17.21, Jgem=1.52, 15Htrans), 5.91 (dd, 1H,
J=3.04, 5.06, 6H), 6.12 (dd, 1H, Jtrans=17.21,
J
cis=11.14, 14H), 7.29 (br s, 5H, 5ÂPhH). Anal. calcd
8,13-Epoxy-6ꢀ-(piperidinomethylcarbonyloxy)acetyloxy-
hydrochloride
for C35H50O9NCl, 0.5 H2O: C, 62.44; H, 7.64; N, 2.08;
Cl, 5.27; found: C, 62.51; H, 7.65; N, 2.36; Cl, 5.31%.
1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-14-en-11-one,
(17). The crude product was puri®ed by ¯ash chroma-
tography with 15% CH3CN±CHCl3 followed by 5%
MeOH±CHCl3. Yield, 41%; m.p., 149±50 ꢁC (MeOH±
dry ether); IR: 3450±3280 (br), 2970 (br), 1765 (br),
1705; 1H NMR: 1.0, 1.09, 1.37, 1.40, 1.56 (5Âs, 15H,
5ÂCH3), 1.60±2.57 (m, 6H, 30-CH2, 40-CH2 & 50-CH2),
2.36 (d, 1H, J=3.04, 5H), 2.49 (d, 1H, Jgem=17.21,
12bH), 3.20 (d, 1H, Jgem=17.21, 12aH), 3.57±3.97
(2Âm, 4H, 20-CH2 & 60CH2), 4.17 (br, 2H, COCH2N),
4.31 (d, 1H, J=5.06, 7H), 4.64 (br, 1H, 1H), 4.74 (s, 2H,
COCH2O), 4.96 (dd, 1H, Jcis=11.14, Jgem=1.82,
15Hcis), 5.15 (dd, 1H, Jtrans=17.21, Jgem=1.82,
15Htrans), 5.91 (br, 1H, 6H), 6.12 (dd, 1H, Jtrans=17.21,
8,13-Epoxy-6ꢀ-[(4-methylpiperazino)methylcarbonyloxy]-
acetyloxy-1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (20).
The crude product was partitioned between cold dil.
HCl and EtOAc. The EtOAc layer containing unreacted
16 and hydrolyzed product B. The aqueous layer was
basi®ed and extracted with EtOAc. The EtOAc layer
was washed with brine, dried over anhydrous Na2SO4.
The pure product was converted into hydrochloride salt
from EtOAc±dry ether. The product was ®nally crystal-
lized from dry MeOH±ether. Yield, 34%; m.p., 161±
62 ꢁC; IR: 3440 (br), 2970 (br), 1765 (br), 1725; 1H
NMR (CDCl3+CD3OD): 1.0, 1.06, 1.40, 1.43, 1.54
(5Âs, 15H, 5ÂCH3), 2.39 (d, 1H, J=3.04, 5H), 2.40 (d,
1H, Jgem=16.71, 12bH), 2.96 (s, 3H, NCH3), 3.20 (d,
1H, Jgem=16.71, 12aH); 3.70, 3.97±4.11 (2Âm, 10H, 20-
CH2, 30-CH2, 50-CH2, 60-CH2 & COCH2N), 4.29 (d, 1H,
J=5.06, 7H), 4.51 (br, 1H, 1H), 4.80 (br, 2H,
COCH2O), 4.97 (dd, 1H, Jcis=10.63, Jgem=1.62,
15Hcis), 5.16 (dd, 1H, Jtrans=17.21, Jgem=1.62,
15Htrans), 5.89 (dd, 1H, J=3.04, 5.06, 6H), 6.16 (dd, 1H,
Jcis=11.14, 14H). Anal. calcd for C29H46O9NCl: C,
59.22; H, 7.88; N, 2.38; Cl, 6.03 ; found: C, 59.42; H,
8.14; N, 2.29; Cl, 5.88%.
8,13-Epoxy-6ꢀ-(morpholinomethylcarbonyloxy)acetyloxy-
1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (18). The crude
product was puri®ed by ¯ash chromatography with 5%
MeOH±CHCl3 and was converted into hydrochloride
salt in EtOAc and HCl±ether. Yield, 40%; m.p., 168±
70 ꢁC (MeOH±dry ether); IR: 3450 (br), 2960 (br), 1765
(br), 1722; 1H NMR: 1.0, 1.1, 1.39, 1.41, 1.57 (5Âs, 15H,
5ÂCH3), 2.39 (d, 1H, J=3.04, 5H), 2.49 (d, 1H,
Jtrans=17.21, Jcis=10.63, 14H). Anal. calcd for
C29H47O9N2Cl, 1.5 H2O: C, 55.27; H, 8.00; N, 4.45; Cl,
5.63; found: C, 55.38; H, 8.25; N, 4.15; Cl, 5.95%.
J
gem=17.21, 12bH), 3.21 (d, 1H, Jgem=17.21, 12aH);
6ꢀ-(3-Dimethylaminopropanoyloxy)acetyloxy-8,13-epoxy-
1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (21). This was
prepared by the treatment of B with 3-dimethylamino
propionic acid in a manner similar to the synthesis of
compound 5. The crude product was puri®ed by ¯ash
chromatography with 5% MeOH±EtOAc followed by
10% MeOH±EtOAc. The pure product was converted
into hydrochloride salt from EtOAc and HCl±dry ether.
Yield, 50%; m.p., 132±33 ꢁC (MeOH±dry ether); IR:
3450 (br), 2975 (br), 1760 (br), 1728; 1H NMR: 1.0,
1.06, 1.37, 1.41, 1.57 (5Âs, 15H, 5ÂCH3), 2.37 (d, 1H,
J=3.04, 5H), 2.48 (d, 1H, Jgem=17.21, 12bH), 2.82,
2.86 (2Âs, 6H, N(CH3)2], 2.99±3.43 (m, 5H,
COCH2CH2N & 12aH); 4.30 (d, 1H, J=5.06, 7H), 4.63
(br, 1H, 1H), 4.69 (s, 2H, COCH2O), 4.95 (dd, 1H,
3.39±3.53 (m, 4H, 30-CH2 & 50-CH2), 4.0 (br, 2H,
COCH2N), 4.03±4.20 (m, 4H, 20-CH2 & 60-CH2), 4.31
(d, 1H, J=4.05, 7H), 4.67 (br, 1H, 1H), 4.77 (br, 2H,
COCH2O), 4.97 (dd, 1H, Jcis=10.13, Jgem=2.03,
15Hcis), 5.16 (dd, 1H, Jtrans=17.21, Jgem=2.03,
15Htrans), 5.91 (dd, 1H, J=3.04, 4.05, 6H), 6.05 (dd, 1H,
Jtrans=17.21, Jcis=10.13, 14H). Anal. calcd for
C28H44O10NCl, 2.5 H2O : C, 53.11; H, 7.48; N, 2.21; Cl,
5.59 ; found: C, 53.15; H, 7.91; N, 2.13; Cl, 5.60%.
8,13-Epoxy-6ꢀ-[(4-phenylpiperidino)methylcarbonyloxy]-
acetyloxy-1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (19).
The crude material was puri®ed by ¯ash chromato-
graphy with 15% CH3CN±CHCl3. The pure product was

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2075±2083
2083
Jcis=10.13, Jgem=1.82, 15Hcis), 5.16 (dd, 1H,
Jtrans=17.21, Jgem=1.82, 15Htrans), 5.89 (dd, 1H,
J=3.04, 5.06, 6H), 6.12 (dd, 1H, Jtrans=17.21,
Jcis=10.13, 14H). Anal. calcd for C27H44O9NCl, 0.5
H2O: C, 56.78; H, 7.94; N, 2.45; Cl, 6.21; found: C,
56,76; H, 8.24; N, 2.10; Cl, 6.16%.
Gregory, D.; Mead, A. Invest. Ophthelmol. Vis. Sci. 1984, 25,
268. (c) Seamon, K. B.; Daily, J. W. Adv. Cyclic Nucleotide
protein Phosphorylation Res. 1986, 20, 1.
3. (a) Khandelwal, Y.; Rajeshwari, K.; Rajagopalan, R.;
Swamy, L.; Dohadwalla, A. N.; deSouza, N. J.; Rupp, R. H. J.
Med. Chem. 1988, 31, 1872. (b) Tatee, T.; Narita, A.; Narita,
K.; Izumi, G.; Takahira, T.; Sakurai, M.; Fujita, A.; Hosono,
M.; Yamashita, K.; Enomoto, K.; Shiozawa, A. Chem. Pharm.
Bull. 1996, 44, 2274.
Acknowledgements
4. Lal, B.; Gangopadhyay, A. K.; Aroskar, V. A.; Dohadwalla,
A. N.; Rupp, R. H. Eur. Pat. EP293814; Chem. Abstr. 1989,
110, 213140x.
The authors gratefully acknowledge Dr. R. H. Rupp for
his interest and encouragement. We also acknowledge
late Dr. A. N. Dohadwalla, Dr. N. K. Dadkar for their
help in pharmacological screening. Dr. P. K. Inamdar
and his group for analytical data.
5. Schnabel, E. Liebigs. Ann. Chem. 1967, 702, 188.
6. Halpern, B.; Nitecki, D. E. Tetrahedron Lett. 1967, 3031.
7. Barlos, K.; Papaioannou, D.; Theodoropoulos, D. J. Org.
Chem. 1982, 47, 1324.
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