U.S. patent application number 09/747499 was filed with the patent office on 2002-06-27 for new podophyllotoxin dimer as dna topoisomerase ii inhibitors, and a process for the preparation therefore.
This patent application is currently assigned to COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH. Invention is credited to Eltepu, Laxman, Kamal, Ahmed, Khanna, Gollapalli Bhasker Ramesh, Mohammed, Arifuddin.
Application Number | 20020082432 09/747499 |
Document ID | / |
Family ID | 25005311 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082432 |
Kind Code |
A1 |
Kamal, Ahmed ; et
al. |
June 27, 2002 |
New podophyllotoxin dimer as DNA topoisomerase II inhibitors, and a
process for the preparation therefore
Abstract
The present invention discloses novel podophyllotoxin dimers
having structural formula I 1 wherein R is H or CH.sub.3 and Z is
an aryl or substituted aryl compound selected from the group
consisting of phenylene, naphthalene, p-terphenyl, dimethoxy
benzidine and diphenyl ether and a process for the preparation of
said novel podophyllotoxin dimers. The new podophyllotoxin dimers,
particularly 4.beta.-arylamino derivatives of the podophyllotoxin
dimers of this present invention are useful as potent inhibitors of
DNA-topoisomorase II and are also useful as antitumour agents.
Inventors: |
Kamal, Ahmed; (Hyderabad,
IN) ; Eltepu, Laxman; (Hyderabad, IN) ;
Mohammed, Arifuddin; (Hyderabad, IN) ; Khanna,
Gollapalli Bhasker Ramesh; (Hyderabad, IN) |
Correspondence
Address: |
Ladas & Parry
26 West 61st Street
New York
NY
10023
US
|
Assignee: |
COUNCIL OF SCIENTIFIC &
INDUSTRIAL RESEARCH
|
Family ID: |
25005311 |
Appl. No.: |
09/747499 |
Filed: |
December 22, 2000 |
Current U.S.
Class: |
549/298 |
Current CPC
Class: |
C07D 493/04
20130101 |
Class at
Publication: |
549/298 |
International
Class: |
C07D 307/77 |
Claims
We claim:
1. Novel podophyllotoxin dimers having structural formula 1
3wherein R is II or CII.sub.3 and Z is an aryl or substituted aryl
compound selected from the group consisting of phenylene,
naphthalene, p-terphenyl, dimethoxy benzidine and diphenyl
ether.
2. A process for preparing new podophyllotoxin dimers as claimed in
claim 1, said process comprising (a) stirring a solution of
aromatic diamine, a base and a phase transfer catalyst in a dry
organic solvent at temperature in the range of 10 to 30.degree. C.;
(b) adding slowly 4.beta. bromo podophyllotoxin to the above
solution; (c) stirring the above reaction mixture continuously for
a time period ranging between 6 to 12 hrs; (d) evaporating the
solvent by known methods; and (e) dissolving the residue in a polar
solvent followed by washing and separating the product by
conventional methods.
3. A process as claimed in claim 2 wherein the aromatic diamine
used are selected from the group consisting of 1,4 phenylene
diamine, 1,5, diamino naphthalene, 4,4'-diamino -p-terphenyl,
3,3'-diamino dimethoxy benzidine, 4,4'-diamino diphenyl ether and
2,6 diamino fluorene.
4. A process as claimed in claim 2 wherein the organic solvent used
is selected from the group consisting of dichloromethane,
chloroform, benzene and tetrahydorfuran.
5. A process as claimed in claim 2 wherein base used is selected
from K.sub.2CO.sub.3, BaCO.sub.3 and Et.sub.3N.
6. A process as claimed in 2, wherein the phase transfer catalyst
used is selected from Bu.sub.4N.sup.+Br.sup.- and
Bu.sub.4N.sup.+T.
7. A process as claimed in claim 2, wherein the reaction was
maintained at -10.degree. C. to room temperature.
8. A process as claimed in claim 2 wherein the stirring was
continued for 6 to 12 h.
9. A process as claimed in claim 1 wherein said column
chromatography carried out using chloroform/methanol,
ethylacetate/hexane and chloroform/acetone/ethylacetate systems as
eluents.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for the synthesis
of new podophyllotoxin dimers as DNA-topoisomerase II
inhibitors.
[0002] The present invention particularly relates to the synthesis
of a new class of 4.beta. arylamino derivatives of the
podophyllotoxin dimers as potent inhibitors of DNA-topoisomerase II
and as useful antitumour agents.
BACKGROUND OF THE INVENTION
[0003] Podophyllotoxin is a plant toxin that inhibits the assembly
of microtubules. It was first isolated from the North American
plant Podophyllum peltatum linnaeus, commonly known as 1880. 13,
29]. The naturally occurring aryltetralin lignans of
podophyllotoxin and desoxypodophyllotoxins have been attempted in
the treatment of human neoplasia. These have been mostly
unsuccessful and complicated by side effects such as nausea,
vomiting, diarrhea and damage to normal tissues [Jardin, I.
Podophylltoxius, in Anticancer Agents Based an Natural Product
Models: Casady, J. M.; Douras, J. D.; Eds; Academic Press: New
York, 1980, pp 319-351]. Extensive structural modifications of
podophyllotoxin ring system have been performed in order to obtain
more potent and less toxic anticancer agents, which resulted in the
synthesis of etoposide and teniposide. These two semi-synthetic
glycoside derivatives of podophyllotoxin have been shown to be
active in the treatment of a number of cancers including symptoms,
acute leukemia, cancers of the lung, ovary, testis, bladder and
brain and kaposis sarcoma associated with the acquired immuno
deficiency syndrome [Sackcett. D. L. Podophyllotoxin, Steganacin
and Cambrafastatin: Natural Products that Bind at the Colchicine
Site of Tubulin, Pharm. Ther. 1998, 59, 163-228].
[0004] Etoposide (VP-16) is a widely used antineoplastic agent. The
mechanism of action of this drug is due to its ability to inhibit
the enzyme DNA-topoisomerase II by stabilizing a cleavable enzyme
DNA complex in which the DNA is cleaved and covalently linked to
the enzyme [Ross, W. Rowe, T.; Glisson, B.; Yalowich J; and Liu, L.
Role of Topoisomerase II in Mediating Podophyllotoxin-Induced DNA
Cleavage Cancer Res.; 1984, 44: 5857-5860].
[0005] The structural modifications or podophyllotoxin and
desoxypodophyllotoxin have led to some non-sugar substituted
analogues particularly nitrogen containing derivatives as
4.beta.-N-alkylamino/aryl- amino compounds of
4'-demethylepipodophyllotoxin. These are as active or more active
than etoposide in their inhibition of the human DNA topoisomerase
II. Amongst these N-linked congenets NPF [4'-0-demethyl-4.beta.-(4"
fluoranilino)-4-desoxypodophyllotoxin] and W-68
[4'-0-demethyl-4.beta.-(4"-nitroanilino)-4-desoxypodophyllotoxin]
have been shown better anticancer activity in their preclinical
studies [Zhang, Y. L. ; Tropsha, A.; Mephenol, A. T.; Lee, K-H, J.
Med Chem 1994, 37, 1460]. NPF is the most active drug which is
having 10-fold more potency in inhibiting human DNA topoisomerase
II and 113 times more activity in cellular protein-DNA complex
formation when compared to etoposide. In the in vitro human tumour
cell lines assay, it has proven to be very active.
[0006] The structure activity relationship studies, revealed the
following features
[0007] (i) the presence of a 4'-phenolic hydroxyl group.
[0008] (ii) maintenance of an intact methylenedioxy system of ring
A
[0009] (iii) the free rotation of E-ring
[0010] (iv) a -N atom containing at C-4.beta.-position.
[0011] The drawbacks of the referred work are that in the treatment
of human neoplasia, they have been found to be mostly unsuccessful
and complicated by the side effects such as nausea vomiting
diarrhea and damage to normal tissues. These significant findings
prompted to synthesize a new class of 4-arylamino derivatives of
the podophyllotoxin dimers as potent inhibitors of
DNA-topoisomerase II and as useful antitumour agents.
OBJECTS OF THE INVENTION
[0012] The main object of the present invention is to provide novel
podophyllotoxin dimers as DNA topoisomerase II inhibitors.
[0013] Another object of the present invention is provide a process
for the synthesis of new podophyllotoxin dimers as DNA
topoisomerase II inhibitors, which obviates the drawbacks as
detailed above.
[0014] Another object of the present invention is to provide a
novel and stereo-selective dimers of the podophyllotoxins and
4'-O-demethylepidophyllotixon in good yields.
[0015] Still another object of the present invention is to provide
the key step for the synthesis of these dimers by direct
nucleophilic substitution of the C 4.beta. bromo intermediates.
SUMMARY OF THE INVENTION
[0016] The above and other objects of the present invention are
achieved by providing the new class of C-4.beta.-arylsubstituted
N-linked dimers of podophyllotoxin and 4'-O-demethyle
pipodophyllotoxins which have been synthesized as DNA-topoisomerase
II inhibitors shown in FIG. 1 of the accompanying drawings.
[0017] Accordingly, the present invention provides Novel
podophyllotoxin dimers having structural formula I 2
[0018] where R is H or CH.sub.3 and Z is an aryl or substituted
aryl compound selected from the group consisting of phenylene,
naphthalene, p-terphenyl, dimethoxy benzidine and diphenyl
ether.
[0019] The present invention also provides a process for preparing
new podophyllotoxin dimers as claimed in claim 1, said process
comprising
[0020] (a) stirring a solution of aromatic diamine, a base and a
phase transfer catalyst in a dry organic solvent at temperature in
the range of -10 to 30.degree. C.;
[0021] (b) adding slowly 4.beta.-bromo podophyllotoxin to the above
solution;
[0022] (c) stirring the above reaction mixture continuously for a
time period ranging between 6 to 12 hrs;
[0023] (d) evaporating the solvent by known methods; and
[0024] (e) dissolving the residue in a polar solvent followed by
washing and separating the product by conventional methods.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING
[0025] FIG. 1 discloses the process for the synthesis of new
podophyllotoxin dimers as DNA-topoisomerase II inhibitors produces
the novel and stereo-selective dimers of the podophyllotoxin in
good yields.
DETAILED DESCRIPTION
[0026] The process for the synthesis of new podophyllotoxin dimers
as DNA-topoisomerase II inhibitors produces the novel and
stereo-selective dimers of the podophyllotoxin in good yields,
wherein, the key step for the synthesis of these dimers is by
direct nucleophilic substitution of C-4.beta.-bromo intermediates,
4.beta.-bromo-podophyllotoxin and 4'-O-demethyl-4.beta.-bromo
podophyllotoxin, which have been reacted with diamino aryl
compounds with or without substitution in a stereo-selective manner
to afford the 4.beta.-N-linked dimers of podophyllotoxin (FIG.
1).
[0027] These bromo intermediates have been prepared by the
bromination of the related podophyllotoxin compounds as described
in the literature [Kuhn, M.; Keller-Juslen, C.; Van wartburg, A.
Helv. Chemica.Acta., 1969, 52, 944].
[0028] In an embodiment of the present invention the naturally
occurring podophyllotoxin lignan was isolated from Podophyllum
peltatum linnaeus.
[0029] In another embodiment of the present invention the synthesis
of 4.beta.-bromo intermediates were carried out from bromination of
podophyllotoxin and 4'-O-demethylepipodophyllotoxin.
[0030] In yet another embodiment of the present invention different
unsubstituted and substituted diamino aryl compounds in 0.3 eq to
0.5 eq was used.
[0031] In still another embodiment of the present invention a
variety of solvents were used for the nucleophilic substitution
step, such as dichloromethane, chloroform, tetrahydrofuran and
benzene.
[0032] In still yet another embodiment of the present invention the
catalytic amount of Bu.sub.4N.sup.+T was used (0.5 eq-1.0 eq) by
stirring the reaction mixture between -10.degree. C. to room
temperature for 6 to 12 h.
[0033] In still another embodiment of the present invention bases
like K.sub.2CO.sub.3, BaCO.sub.3, Et.sub.3N were used.
[0034] In still another embodiment of the present invention the
purification of dimers was done by column chromatography using
chloroform/methanol, ethylacetate/hexane, and
chloroform/acetone/ethylace- tate etc.
[0035] Thus the present invention provides a new class of
podophyllotoxin dimers have been synthesized in a stereoselective
manner.
[0036] The following examples are given by way of illustrations and
therefore should not be construed to limit the scope of the
invention.
[0037] Experimental
[0038] Typical Procedure:
[0039] Preparation of C-4.beta.-bromo/4'O-demethyl podophyllotoxin:
Hbr was passed thorough a solution of podophyllotoxin (414 mg, 1
mmol) or 4'-O-dementhyl podophyllotoxin (400 mg, 1 mmol) in
dichloromethane (20 ml) at 0.degree. C. for 45 minutes. After the
completion of reaction, the solvent was evaporated in vacuum, which
was then used for the next reaction with aryl amines without
further purification.
EXAMPLE 1
[0040] 1",4"-[Bis-(4.beta.-N-podophyllotoxin)] phenylene diamine
(3a): To a stirred solution of 1,4-phenylene diamine (54 mg, 0.5
mmol), Et.sub.3N (150 mg, 1.5 mmol) and Bu.sub.4N.sup.+T (185 mg,
0.5 mmol) in dry THF (10 ml) at room temperature, a solution of
4.beta.-bromo podophyllotoxin (476 mg, 1.0 mmol) in THF (20 ml) was
added slowly at room temperature under nitrogen atmosphere. The
stirring was continued for 6 hr. After completion of the reaction,
as indicated by TLC, the THF was evaporated under reduced pressure.
The residue was dissolved in the chloroform and washed with water.
This was then subjected to column chromatography on silicagel using
chloroform: acetone: ethylacetate (9.5: 0.5: 0.5) as eluents in the
pure dimer in 80% yield.
[0041] Spectral data: .sup.1H NMR(CDCl.sub.3); 6.78 (S, 2H), 6.50
(S, 2H), 632-645 (d, 4H), 6.26 (S, H) 5.90-6.00 (ABq, 4H),
4.50-4.61 (br, 4H), 4.28-4.40 (d, 2H), 3.98-4.10 (t, 2H), 3.70-3.80
(d, 18H), 3.40-3.60 (br,2H), 3.07-3.22 (dd, 2H), 2.82-3.05 (m, 2H);
FAB MS: m/z 900 (M.sup.+); mp. 197-199.degree. C.
EXAMPLE 2
[0042] 1",5"-[Bis-(4.beta.-N-podophyllotoxin)] naphthalene
diamine(4a) was prepared according to the method described for the
compound 3a, employing the 1,5-diamino naphthalene (80 mg, 0.5
mmol), Bu.sub.4N.sup.+T (185 mg, 0.5 mmol), Et.sub.3N (150 mg, 1.5
mmol) and 4.beta.-bromopodophyllotoxin (476 mg, 1.0 mmol) to give
4a in the 78% yield.
[0043] Spectral data: .sup.1H NMR(CDCl.sub.3): 733-743 (d, 2H),
7.16-7.28 (t, 2H), 6.78 (S, 2H), 6.56-6.63 (d, 2H), 6.53 (S, 2H),
6.33 (S, 4H), 5.90-600 (ABq, 4H), 5.49-5.59 (br, 2H, NH), 4.92-5.05
(br, 2H), 4.55-4.64 (d, 2H), 4.34-4.48 (t, 2H), 3.80-4.93 (t, 2H),
3.75 (S, 18H), 3.49-3.65 (dd, 2H), 2.95-3.10 (m, 2H), FAB MS. m/z
951 (M.sup.+1), mp. 227-230.degree. C.
EXAMPLE 3
[0044] 4",4'" [Bis(4.beta.-N-podophyllotoxin)] p-terphenyl diamine
(5a) was prepared according to the method described earlier,
employing 4,4'-diamino-p-terphenyl (130 mg, 0.5 mmol),
Bu.sub.4N.sup.+T (185 mg, 0.5 mmol), Rt.sub.3N (150 mg, 1.5 mmol)
and bromo podophyllotoxin (476 mg, 1.0 mmol) to give the product in
75% yield. Spectral data: .sup.1HNMR (CDCl.sub.3); 7.63 (d, 4H),
7.50-7.58 (d, 4H), 6.88 (S, 2H), 6.62-6.72 (d, 4H), 6.60 (S, 2H),
6.37 (S, 4H), 6.00-6.08 (ABq, 4H), 4.78 (br, 2H), 4.62-4.70 (d,
2H), 4.42-4.53 (t, 2H), 4.03 4.18 (t, 2H), 3.92-4.09 (d, 2H), 3.86
(d, 18H), 3.16-3.28 (dd, 2H), 2.97-3.13 (m,2H); FAB MS: m/z 1052
(M.sup.+); mp. 203-206.degree. C.
EXAMPLE 4
[0045] 3",-3'"- [Bis-(4.beta.-N-podophyllotoxin)]diamino dimethoxy
bonzidine (6a) was prepared by the same procedure described earlier
using 3,3' diamino-dimethoxy benzidine (122 mg, 0.5 mmol)
Bu.sub.4N.sup.+T (185 mg, 0.5 mmol), Et.sub.3N (150 g, 1.5 mmol)
and 4.beta.-bromo podophyllotoxin (476 mg, 10 mmol) to give the
product in 78% yield Spectral data: .sup.1H NMR (CDCl.sub.3);
6.98-7.05 (d, 2H), 6.94 (S, 2H), 6.78 (S, 2H), 6.55 (S, 2H),
6.45-6.52 (d, 2H), 6.32 (S,4H) 5.99 (AB.sub.4, 4H), 4.70 (br, 2H),
4.60-4.67 (d, 2H), 4.34-4.49 (t, 2H), 4.00 (t,2H), 3.93 (S,6H),
3.80 (d, 18H), 3.13 3.28 (dd, 2H), 2.90 3.12 (m, 2H); FAB MS: m/z
1036 (M.sup.-); mp. 204-207.degree. C.
EXAMPLE 5
[0046] 4",4'"-[bis-(4.beta.-N-podophyllotoxin)] diamino
diphenylether (7a) was synthesized by the method described for
earlier compounds employing, 4,4'-diamino diphenylether (100 mg,
0.5 mmol), bromopodophyllotoxin (476 mg, 1.0 mmol) Bu.sub.4N.sup.+T
(185 mg, 0.5 mmol) and Et.sub.3N (150 mg, 1.5 mmol) to give 7a in
78% yield. Spectral data: .sup.1H NMR (CDCl.sub.3); 6.81-6.90 (d,
4H), 6.79 (S, 2H), 649-6.53 (d, 4H), 6.47 (S, 2H), 6.29 (S, 4H),
5.95-6.00 (ABq, 4H), 4.56-4.63 (d, 4H), 4.34-4.45 (t, 2H),
3.98-4.10 (t, 2H), 3.74-3.82 (d, 18H), 3.67-3.72 (d,2H), 3.10-3.21
(dd, 2H), 2.91-3.07 (m, 2H); FAB MS: m/z 993 (M.sup.+1); mp.
201-204.degree. C.
EXAMPLE 6
[0047] 2",7"-[Bis-(4.beta.-N-podophyllotoxin)] diaminofluorene (8a)
was prepared by the same method described earlier, employing
2,7-diamino flourene (135 mg, 0.5 mmol), Bu.sub.4NT (185 mg, 0.5
mmol) and Et.sub.3N (150 mg, 1.5 mmol) and 4.beta.-bromo
podophyllotoxin (476 mg, 1.0 mmol) to give 8a in 75% yield Spectral
data: .sup.1H NMR (CDCl.sub.3); 7.39-7.50 (d, 2H), 6.82 (S, 2H),
6.68 (S, 2H), 6.45-6.58 (br, 4H), 6.31 (S, 4H), 5.92-6.01 (ABq,
4H), 4.71 (br, 2H), 4.60 (d, 2H), 4.38-4.48 (t, 2H), 4.00-4.13 (t,
2H), 3.80 (d, 18H), 3.10-3.22 (dd, 2H), 2.90-3.10 (m, 2H); FAB MS:
m/z 988 (M.sup.+); mp. 215-218.degree. C.
EXAMPLE 7
[0048]
1",4"-Bis-(4'-O-dementhyl-4.beta.-N-4-desoxypodophyllootoxin)]Pheny-
lene diamine (3b) was synthesized by the procedure described for
earlier compounds, employing 1,4-phenylene diamine (54 mg, 0.5
mmol), Bu.sub.dN.sup.+T (185 mg, 0.5 mmol), Et.sub.3N (150 mg, 1.5
mmol), and 4'-O-dementyl-4.beta.-bromo-4-desoxy-podophyllotoxin
(462 mg, 1.0 mmol) to give the product in 76% yield. Spectral data:
.sup.1H NMR (CDCl.sub.3); 6.72-6.85 (m, 4H), 6.46 (S,2H), 6.36 (S,
2H), 6.22-6.30 (S, 4H), 5.88-5.98 (ABq. 4H), 5.34 (S, 2H), 4.52
(br, 2H), 420-4.40 (t, 2H), 3.90-4.10 (t,2H), 3.75 (S, 6H),
3.16-3.35 (m, 4H); FAB MS: m/z 872(M.sup.+); mp. 216-219.degree.
C.
EXAMPLE 8
[0049]
1",5"-[Bis-(4'-O-demethyl-4.beta.-N-4-desoxypodophyllotoxin)]
naphthalene diamine (4b) was prepared according to the method
described earlier, employing 1,5-diamino naphthalene (80 mg, 0.5
mmol), Bu.sub.4N.sup.+T (185 mg, 0.5 mmol), Et.sub.3N (150 mg, 1.5
mmol) and 4'-O-demethyl-4.beta.-bromo-4-desoxy podophyllotoxin (462
mg, 1.0 mmol) to give the product in 76% yield. Spectral data:
.sup.1H NMR (CDCl.sub.3); 7.22-7.28 (d, 2H), 7.10-7.19 (t, 2H),
6.73 (S, 2H), 6.58 (S, 2H), 6.50 6.55 (d, 2H), 6.33 (S, 4H), 5.98
(ABq, 4H), 5.34 (S, 2H), 4.87 (br, 2H), 4.63 4.70 (d, 2H), 4.52
4.59 (d, 2H), 436-4.48 (t, 2H), 3.85-3.95 (d, 2H), 3.82 (3, 6H),
3.20-3.31(dd, 2H), 2.98-3.16(m, 2H); FAB MS: m/z 922 (M.sup.+); mp
238-240.degree. C.
EXAMPLE 9
[0050]
4",4'"-[Bis-(4'-O-demethyl-4.beta.-N-4-desoxypodophyllotoxin)]-p-te-
rphenyl diamine (5b) was prepared according to the method described
earlier, employing 4,4'-diamino-p-terphenyl (130 mg, 0.5 mmol),
Bu.sub.4NT (185 mg, 0.5 mmol), Et.sub.3N (150 mg, 1.5 mmol) and
4'-O-diemthyl-4.beta.-bromo podophyllotoxin (462 mg, 1.0 mmol) to
give the product in 72% yield. Spectral data: .sup.1H NMR
(CDCl.sub.3); 7.57 (S, 4H), 7.42-7.52 (s, 4H), 6.81 (S, 2H),
6.58-6.67 (d, 4H), 6.55 (S, 2H), 6.32 (S, 4H), 5.98 (Abq, 4H), 5.35
(S, 2H), 4.70-4.78 (br, 2H), 4.60 (d, 2H), 435-4.48 (t, 2H),
4.00-4.11 (t,2H), 3.90 (br, 2H) 3.82 (S, 6H), 3.10-3.21 (dd 2H),
2.94-3.08 (m, 2H); FAB MS: m/z: 1024(M.sup.+); mp. 226-229.degree.
C.
EXAMPLE 10
[0051]
3",3'"-[Bis-(4'-O-demethyl-4.beta.-N-4-desoxypodophyllotoxin)]
dimethoxy benzidine (6b) was prepared according to the method
described for earlier compounds, employing 3,3'-dimethoxy benzidine
(122 mg, 0.5 mmol), Bu.sub.4N+T.sup.- (185 mg, 0.5 mmol), Et.sub.3N
(150 mg, 1.5 mmol) and 4'-O-demethyl-4.beta.-bromo podophyllotoxin
(462 mg, 1.0 mmol) to give the product in 70% yield. Spectral data:
.sup.1H NMR (CDCl.sub.3), 7.00-7.08 (d, 2H), 6.97 (S, 2H), 6.81 (S,
2H), 6.58 (S, 2H), 6.49-6.55 (d, 2H), 6.36 (S, 4H), 6.01 (ABq, 4H),
5.40 (S, 2H), 4.73 (br, 2H), 4.62-4.68 (d, 2H), 4.37-4.50 (m,
4H),4.00-4.10 (t, 2H), 3.95 (S, 6H), 3.84 (S, 6H), 3.18-3.30 (dd,
2H), 2.98-3.15 (m, 2H); FAB MS: m/z 1008 (M.sup.+), mp.
215-218.degree. C.
EXAMPLE 11
[0052] 4",4'" [Bis(4' O
demethyl-4.beta.-N-4-desoxypodophyllotoxin)] diamino diphenylether
(7b) was prepared by the same procedure described earlier,
employingg 4,4' diamino diphenylether (100 mg, 0.5 mmol),
Ru.sub.4N.sup.+T (185 mg, 0.5 mmol), Ft.sub.3N (150 mg, 1.5 mmol)
and bromo compound (462 mg, 1.0 mmol) to give the product in 75%
yield. Spectral data: .sup.1H NMR (CDCl.sub.3); 6.85 6.95 (d, 4H),
6.81 (8, 2H), 6.55 (S, 2H), 6.48 6.54 (d, 4H), 6.34 (S, 2H), 6.01
(ABq. 4H), 5.39 (S, 2H), 4.59-4.69 (m, 4H), 4.35-4.45 (t, 2H),
4.00-4.12 (t, 2H), 3.86 (S, 6H), 3.68-3.76 (d,2H), 3.11-3.23 (dd,
2H), 2.94-3.10 (m, 2H); FAB MS: m/z 964 (M.sup.+); mp.
217-219.degree. C.
EXAMPLE 12
[0053] 2",7"-[Bis-(4'-O demethyl-4.beta.-N-4
desoxypodophyllotoxin)] diamino flourene (8b) was prepared
according to the procedure described for the earlier compounds,
employing 2,7-diamino flourene (135 mg, 0.5 mmol), Bu.sub.4N.sup.+T
(185 mg, 0.5 mmol), Et.sub.3N (150 mg, 1.5 mmol) and
4'-O-demethyl-4.beta.-bromo podophyllotoxin (462 mg, 1.0 mmol) to
give the product in 70% yield. Spectral data: .sup.1H NMR
(CDCl.sub.3); 7.39-7.45 (d, 2H), 6.78 (S, 2H), 6.66 (S, 2H), 6.50
(S, 2H), 6.43-6.48 (d, 2H), 6.30 (S, 4H), 5.92-6.00 (ABq, 4H), 5.33
(S,2H), 4.70 (br, 2H), 455-4.61 (d, 2H), 433-4.45 (t, 2H),
3.97-4.10(t,2H), 3.79 (S, 6H), 3.08-3.20 (dd, 2H), 2.90-3.08 (m,
2H); FAB MS: m/z 960 (M.sup.-); mp. 240-243.degree. C.
[0054] In conclusion, the main advantages of the present inventions
are
[0055] 1. A new class of podophyllotoxin and
4'-O-demethylepipodophyllotox- in dimers have been synthesized as
DNA-topoisomerase II inhibitors.
[0056] 2. These novel dimers have been synthesized in good yields
and high stereoselective manner.
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