WO1998025910A1 - NEW DERIVATIVES OF 6-[(AMINOALKYL)AMINO]-7H-BENZO[e]-PERIMIDIN-7-ONE, METHOD OF THEIR PREPARATION, AND THEIR USE AS A MEDICAMENT - Google Patents
NEW DERIVATIVES OF 6-[(AMINOALKYL)AMINO]-7H-BENZO[e]-PERIMIDIN-7-ONE, METHOD OF THEIR PREPARATION, AND THEIR USE AS A MEDICAMENT Download PDFInfo
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- WO1998025910A1 WO1998025910A1 PCT/PL1997/000031 PL9700031W WO9825910A1 WO 1998025910 A1 WO1998025910 A1 WO 1998025910A1 PL 9700031 W PL9700031 W PL 9700031W WO 9825910 A1 WO9825910 A1 WO 9825910A1
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- benzo
- ethyl
- amιno
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- peπmιdιn
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- the invention i elates to new derivatives of 6-[ aminoalkyl)amino]-7H-benzo[e]-
- R2 is hydrogen, methyl, ethyl, isopropyl group
- n stands for 2 or 3, method of then preparation, and their use as a
- mitoxantrone A serious problem of phenotypic, multidrug cross resistance (MDR) of tumoi
- MDR tumor cells
- mice leukemia P388 (B Stefanska et al J. Med. Chem. 36, 38 (1993)).
- the compounds posses cytotoxic activity in vitro against mice leukemia cells
- silica gel was used as the bed) in benzene - acetone (2 1 ) solvent system
- the pine compound is obtained as a dark-che ⁇ y powder of melting point > 300
- N,N.N',N'-tetramethylethylened ⁇ am ⁇ ne is refluxed under nitrogen atmosphere for
- dimethylammopropylamine is stirred and heated at 135 °C, under nitrogen
- hydrochlo ⁇ de is 24 % of theory, melting point 181 - 185 °C, decomp ⁇ NMR
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to new derivatives of 6-[(aminoalkyl)amino]-7H-benzo[e]-perimidin-7-one of general formula (1), wherein R1 stands for hydrogen, methyl, ethyl, hydroxyethyl group, R2 is hydrogen, methyl, ethyl, isopropyl group, and character n stands for 2 or 3. In other aspects, the invention relates to the process for preparation of the compounds, and their use in treatment of tumor diseases.
Description
New derivath es of 6-[(aminoalkyl)amino]-7H-benzo[e]-perimidin-7-one,
method of their preparation, and their use as a medicament
The invention i elates to new derivatives of 6-[ aminoalkyl)amino]-7H-benzo[e]-
peπmιdιn-7-one of general formula 1 , wherein R\ stands for hydrogen, methyl,
ethyl, hydiox) ethyl gioup, R2 is hydrogen, methyl, ethyl, isopropyl group, and
character n stands for 2 or 3, method of then preparation, and their use as a
medicament
Synthetic de atives and analogs of antraquinone constitute a valuable group of
potential antitumor drugs Among many synthetised and tested substances of this
type, 1.4-dιhydroxy-5.8-bιs[2-[(2-hydroxyethylammo)ethyl]ammo]-9, 10-
anthracenedione has been used in clinic under the commercial name
mitoxantrone
A serious problem of phenotypic, multidrug cross resistance (MDR) of tumoi
cells to many, structurally and mechanistically diverse cytostatic agents, has
appeared during the last decade The phenomenon results in the loss of
therapeutic value of numerous groups of antitumor drugs, including mitoxantrone
itself. In result, there is a need for the development of new antitumor compounds,
active against the resistant cells
Among numerous, newly synthesized analogs of mitoxantrone, there is an
important group of derivatives possessing an additional heterocychc ring, forming
a part of chromophoπc system, for example anthrapyrazoles (H Showalter et al.
Anti-Cancer Drug Des. 1, 73 (1986), pyridines (P. Krapcho et al. J Med Chem.
37, 823 ( 1994), or pyπdazines (C Gandolfi et al J Med Chem 38, 526
(1995))
Some of them demonstrate in vitro certain activity against multidrug resistant
tumor cells (MDR, line LoVo/Dx)
There are know n analogs of 6-[(amιnoalkyl)amιno]-7//-benzo[e]-peπmιdιn-7-
one, prepared as analogs of ametantrone (deoxy-mitoxantrone), possessing
additional pyπmidine ring, which exhibit significant antileukemic activity against
mice leukemia P388 (B Stefanska et al J. Med. Chem. 36, 38 (1993)).
Until now, 8, 1 1 -dιhydroxy derivatives of 6-[(amιnoalkyl)amιno]-7 /-benzo[e]-
penmιdιn-7-one have been unknown
According to the present invention, new denvatives of 6-[(amιnoalkyl)amιno]-
7 -benzo[e]-peπmιdιn-7-one are presented by formula 1 , wherein Ri stands for
hydrogen, methvl, ethyl, hydroxyethyl group, and R2 is hydrogen, methyl, ethyl,
isopropyl group, and character n stands for 2 or 3
According to the present invention, a method of preparation of new derivatives
of 6-[(amιnoalkyl)amιno]-7//-benzo[e]-peπmιdιn-7-one is characterized by
heating of 5,8-bιs(benzyloxy)-l ,4-dιamιno-9,10-antracenedιone in
dimethylacetamide with formamide in the presence of catalyst, preferably
ammonium metavanadate, at reflux temperature for 20-60 minutes, treatment of
the 6-ammo-8,l l -bιs(benzyloxy)-7//-benzo[e]peπmιdιn-7-one, isolated from the
reaction mixtuie. with tπfluoroacetic acid at room temperature, subsequent
heating of 6-amιno-8,l l -dιhydroxy-7 7-benzo[e]peπmιdιn-7-one, isolated from
the reaction mixture, with aminoalkylamine suitable for the end product,
preferably with addition of N,N,N',N'-tetramethylethylenedιamme and small
amount of water, under neutral gas atmosphere, at boiling temperature for 2 - 15
hours, and isolation and purification of the product, preferably by silica gel
column cliromatography, and eventual transformation into its pharmaceutically
acceptable salt
Method of piepaiation of derivatives of 6-[(amιnoalkyl)amιno]-7//-benzo[e]-
peπmιdιn-7-one accordmg to the invention, is shown on Scheme 1 , wherein Bn
represents benz\ l, DMA- dimethylacetamide, TFA - tπfluoroacetic acid
Compounds accordmg to the invention demonstrate in vitro much higher
cytotoxic activity against mice leucemia L1210 cells than their deoxy analogs
Unexpectedly, these compounds exhibit high cytotoxic activity against multidrug
resistant human adenocarcinome cell line Doxorubicm resistant (LoVo Dx) In
the above tests, the highest activity was demonstrated by 8,1 l -dιhydroxy-6-[2-
(dιmethylamιno)ethylamιno]-7//-benzo[e]-peπmιdιn-7-one, called further BP-1 ,
and shown on Fig 2 The compound demonstrates also high cytotoxic activity
against broad spectmm of human tumor cells Compound BP-1 posses also high
chemotherapeutic activity in vivo against leukemia P388
The compounds posses cytotoxic activity in vitro against mice leukemia cells
LI 210, and on human adenocarcinome cell lines, both Doxorubicm sensitive and
resistant (LoVo LoVo/Dx) The results are shown in Tables 1 and 2 In these
tests, the highest activity was also found for compound BP-1 which
demonstrates also high cytotoxic activity against broad spectrum of human tumor
cells, as shown in Table 3 In treatment of mice leukemia P388, compound BP-1
demonstrated higher activity, and in lower doses, than its deoxy analog, as shown
in Table 4
The invention is illustrated by the examples below
Example 1
0,45 g (ImM) of 5,8-bιs(benzyloxy)-l ,4-dιamιno-9,10-anthracenedιone, 0 45 g
of ammonium metavanadate, 1 ,5 ml of formamide in 15 ml of dimethylacetamide
are intensively stirred and refluxed for 30 minutes The progress of the reaction
is followed by thin layer chromatography on silica gel in toluene - acetone (2 1 )
solvent system The product of the reaction demonstrates fluorescence under 360
nm UN light The reaction mixture is cooled, the crude product is precipitated
with cold water and well washed with hot water The product is purified on silica
(Merck silica gel 60, 70-230 mesh) chromatography column in chloroform -
methanol 50 1 solvent system to give 0 14 g (31 % of theory) of pure 6-amιno-
8,1 l -bιs(benzyloxy)-~ 7-benzo[e]peπmιdιn-7-one as an orange powder, melting
point 231 - 233 °C !H ΝMR (CDC13) δ 5 22 (s, 2H), 5 3 (s,2H), 7 25 (d, 1H, J =
9,19), 7,3 - 7,5 (m , 1 1 H), 7 6 - 7,7 (m , 2H), 8,05 (d, 1 H, J = 9 24), 9,4 (s, 1 H)
MS-FD m/z (i elativ e intensity %) 458 ([M- l ]\ 50), 459 ( [MT\ 100), 460
([M+l ]+, 50)
459 mg (I mM) of 6-ammo-8, l l -bιs(benzyloxy)-7 7-benzo[e]peπmιdm-7-one in 5
ml of tπfluoroacetic acid is left at room temperature for 10 hours Next the
reagent is removed under reduced pressure with addition of benzene to give 265
mg (95 ° o of theory) of crude 6-amιno-8.1 l -dιhydroxy-7/ -benzo[e]peπmιdιn-7-
one Analytical sample was purified by column chromatography (similarly as
above, silica gel was used as the bed) in benzene - acetone (2 1 ) solvent system
The pine compound is obtained as a dark-cheπy powder of melting point > 300
°C ]H NMR (d6-DMSO) δ 7 2 (d, 1H, J = 9 0), 7 35 (d, 1H, J = 9 05), 7 65 (d,
1 H, J = 8 0). 8 1 (d, 1 H, J = 8 1 ), 9 2 (s, 1 H), 13 5 (s, 1 H, D20 exchangeable).
13 82 (s, 1 H, D:0 exchangeable) MS-FD m/z (relative intensity %) 279 ([MY,
100)
280 mg ( I mM) of 6-amιno-8, l l -dιhydroxy-7//-benzo[e]peπmιdιn-7-one, 6 ml of
2-dιmethylammoethylarnme, 2 ml of N,N,N',N'-tetramethylethylenedιamιne, and
0.8 ml of water is stirred and heated at 135 °C under nitrogen atmosphere for 5
hours. The progress of the reaction is followed by thin layer chromatography on
silica gel in chloroform - methanol (10 : I ) solvent system. The reaction mixture
is diluted with chloroform, and next washed with diluted hydrochloric acid and
water to remove excess of amines. The organic layer is dried over Na2S04,
solvents are evaporated under reduced pressure, and the residue is
chromatographed on column (silica gel bed) in chloroform - methanol (10 : 1 ),
and subsequently chloroform - methanol (5 1 ), chloroform - methanol - 25 %
aqueous ammonia (5 1 0.1 ) Pure 8, 1 l -dιhydroxy-6-[[(2-
dimethylamino)ethyl]amιno]-7//-benzo[e]peπmidin-7-one is transformed into its
hydrochloπde using etheral solution of hydi ochloπde The yield of the isolated
product is 36 %. melting pomt 194 - 197 °C. Η NMR (d6-DMSO) δ 2.8 (s, 6H);
4 5 (m . 4H), 7 25 (d, 1 H, J = 9 0), 7 4 (d, 1 H. J = 9 0), 8 05 (d, 1 H, J = 9.1 ), 8 2
(d, 1H, J = 9.0), 9.3 (s, 1 H); 10.8 (m„ 1H, D20 exchangeable), 13.4 (s, 1H, D20
exchangeable); 14.0 (s, 1H, D20 exchangeable). MS-FD m/z (relative intensity
%) 349 ([M- l ]\ 30), 350 ([M]+, 100).
Example 2.
280 mg (ImM) of 6-amιno-8, l l -dihydroxy-7//-benzo[e]perimιdιn-7-one,
prepared as described in Example 1 , 6 ml of 2-dιethylamιnoethylamιne, 2 ml of
N,N.N',N'-tetramethylethylenedιamιne, is refluxed under nitrogen atmosphere for
3 hours. Subsequent procedure is identical as in Example 1 , to give 8, 1 1 -
dιhydroxy-6-[(2-dιethylamιno)ethyl]amιno-7//-benzo[e eπmιdιn-7-one
hydrochloπde in 50 % yield, meltmg point 197 - 200 °C Η NMR (d6-DMSO)
δ 1 25 (t, 6H, J = 7), 3 1 - 3 4 (m , 4H), 4 2 (m , 4H), 7 25 (d, 1H, J = 9 0), 7 45
(d, 1H, J = 9 0), 8 05 (d, 1H, J = 9 0), 8 2 (d, 1 H, J = 9 0), 9 3 (s, 1H), 10 9 (m ,
1H, D20 exchangeable), 13 8 (s, 1H, D20 exchangeable) MS-FD m/z (relative
intensity %) 378 ([M] 100), 379 ([M+ l f, 60)
Example 3
140 mg (0 5ιnM) of 6-amιno-8.1 l -dιhydroxy-7//-benzo[ ]peπmιdιn-7-one.
prepared as described in Example 1 , 2 ml of 2-(2-hydroxyethyl)ammoethylamιne,
0 2 ml of water, and 1 ml of N,N,N',N'-tetramethylethylenedιamιne, is stirred and
heated at 135 °C under nitrogen atmosphere for 4 hours The reaction mixture is
diluted with chloroform, and next washed with diluted hydrochloric acid and
watei to remov e excess of amines Next, the product is extracted with I N
hydrochloric acid, and the extract neutralized with sodium bicarbonate to pH = 8
- 9 The product is extracted out of the aqueous layer with chloroform - methanol
9 1 mixture The organic layer is dried over Na S04, the solvents are
evaporated under reduced pressure, and the residue is chromatographed on
column (silica gel bed as above) using solvent system as in Example 1 Pure
8,1 l -dιhydroxy-6-[[2-[(2-hydroxyeth>l)amιno]ethyl]amιno]-7 /-
benzo[e]peπmιdιn-7-one is transfoπried into its hydrochloπde as described in
Example 1 The vield of the isolated product is 40 %, melting point > 300 °C Η
NMR (d6-DMSO) δ 3 0 - 3 2 (m, 4H), 3 5 (q , 2H, J = 6 2), 3 7 (t, 2H, J = 5 1),
7 2 (d, I H, J = 9 1 ), 7 3 (d, I H, J = 10 2), 7 4 (d, I I I, J = 9 6), 8 0 (d, IH, J =
9 5), 9 2 (s, IH), 11 5 (m , IH, D20 exchangeable), 13 4 (s, IH, D20
exchangeable), 13 8 (s, I H, D20 exchangeable) MS-FD m/z (relative intensity
%) 366 ([MΓ, 100)
Example 4
Reaction of 140 mg (0 5mM) of 6-amιno-8,l l -dιhydroxy-7//-benzo[e]peπmιdιn-
7-one, prepared as described in Example 1 , with 2 ml of 2-
(ιzopropv lamιno)ethylamιne, in 1 ml of N,N,N',N'-tetramethylethylenedιamιne
with small addition of water, is performed for 14 hours at 125 - 130 °C, with
stirring and under nitrogen atmosphere Subsequent procedure is analogous to
that described in Example 1 Pure 8,l l -dιhydroxy-6-[[(2-
ιzoprop) lamιno]ethylamιno]-"//-benzo[e]peπmιdιn-7-one is transformed into its
hydrochloπde as described in Example 1 1 10 mg (55 % of theory) of the product
is obtained, melting point > 300 °C Η NMR (d6-DMSO) δ 1 2 (d, 6H, J = 6 8),
3 2 - 3 3 (m, I H), 3 95 - 4 15 (m, 4H), 7 2 - 7 4 (m, 2H), 8 0 - 8 2 (m , 2H), 8 9 -
9 1 (m, IH, D20 exchangeable), 10 8 (m, I H. D20 exchangeable), 1 1 4 (s , IH,
D20 exchangeable), 13 9 (s, I H, D20 exchangeable) MS-FD m/z (relative
intensi %) 364 ([M]\ 100)
Example 5
Reaction of 140 mg (0 5mM) of 6-amιno-8,l l -dιhydroxy-7 /-benzo[e]peπmιdιn-
7-one, prepared as described in Example 1 , with 2 ml of 2-
(ethylamιno)ethylamιne, in 1 ml of N,N,N',N'-tetramethylethylenedιamιne with
small addition of water, is perfoπried for 12 hours at 100 - 105 °C, with stirring
and under nitrogen atmosphere Subsequent procedure is analogous to that
described in Example 1 Pure 8,l l-dιhydroxy-6-[[(2-
ιzopropylamιno]ethylaιnιno]-7iL -benzo[e]peι ιmιdιn-7-one is tiansformed into its
hydrochloπde as described in the Example 1 46 5 mg (24 % of theory) of
product is obtained, melting point > 300 °C Η NMR (d6-DMSO) δ 1 1 (t, 3H, J
= 6 5), 2.68 (q, 2H, J = 6.0); 3 9 - 4.05 (m, 4H), 7.2 - 7 4 (m, 2H), 8 0 - 8 15 (m ,
2H), 8 6 - 8 7 (m, I H, D20 exchangeable), 9 3 (s, I H), 10 8 (m, IH, D20
exchangeable), 1 1 35 (s , IH, D20 exchangeable) MS-FD m/z (relative intensity
%) 350 ([M]+, 100)
Example 6
A sample of 140 mg (0 5mM) of 6-amιno-8,l 1 -dιhydroxy-7/7-benzo[e]peπmιdιn-
7-one, prepared as described in Example 1 , and 5 ml of 3-
dimethylammopropylamine, is stirred and heated at 135 °C, under nitrogen
atmosphere for 3 hours Subsequent procedure is analogous to that described in
Example 1 The yield of 8, 1 l -dιhydroxy-6-[[3-(dιmethylammo)propyl]amιno]-
7/7-benzo[e]pernnιdιn-7-one hydrochloπde is 42 % of theory, melting point 196 -
198 °C 'H NMR (d6-DMSO) δ 1.85 (m, 2H), 2 2 (s, 6H), 2 36 (t, 2H), 3 58 (m ,
2H), 7 25 (d, IH, J = 9 0), 7 45 (d , I H, J = 9 0), 8 2 (d, IH, J = 9 0), 9 3 (s,
I H), 10 75 (m, I H, D20 exchangeable), 12 3 (s , I H, D20 exchangeable), 13 8
(s., IH, D20 exchangeable) MS-FD m/z (relative intensity %) 364 ([M]+, 100)
Example 7
Reaction of 140 mg (0 5mM) of 6-amιno-8,l l -dιhydroxy-7//-benzo[e]peπmιdιn-
7-one, prepared as desciibed in Example 1. and 5 ml of ethvlenediamine, is
heated at 60 - 65 °C, under nitrogen atmosphere for 1 5 hours Subsequent
procedure is analogous to that described in Example 1 The yield of 8,1 1-
dιhydroxy-6-[[3-(dιmethylamιno)propyl]ammo]-7//-benzo[e]peπmιdιn-7-one
hydrochloπde is 24 % of theory, melting point 181 - 185 °C, decomp Η NMR
(dft-DMSO) δ 3 12 (t, 2H, J = 7 0), 3 95 (q, 2H, J = 7 0), 7 25 (d, I H, J = 9 0),
7 45 (d , IH, J = 9 0), 8 10 (d, IH, J = 9 0), 8 25 (d, I H, J = 9 0), 8 3 (broad s,
2H, D20 exchangeable), 9 3 (s, I H). 1 1 10 (m , I H, D20 exchangeable), 14 05
(s , IH, D20 exchangeable) MS-FD m/z (relative intensity %) 349 ([M -1]+, 50),
350 ([M]+, 100), 351 ([M +l]\ 50)
Table 1
In vitro cytotoxic activity of 6-[(aminoalkyl)amino]-7-//-benzo[e]- perimidin-7-one derivatives against murine leukemia L1210 cells
EC50 - Inhibiting concentration of 50% cellular growth ± SEM
Table 2
In vitro cytotoxic activity of BP-1 in comparison with Ametantrone and Mitoxantrone on human adenocarcinoma cell lines sensitive
(L0V0) and Doxorubicin resistant (LoVo/Dx).
EC50 - Inhibiting concentration of 50% cellular growth ± SEM RI - Resistant index = EC ) L0V0/DX / EC5(, L0V0
Table 3
In vitro cytotoxic activity of BP-1 (NSC 669967) on cancer human cell lines according National Cancer Institute, Bethesda
(selected data)
Panel/L mia GIso (μM)
Leukemia
CCRF-CEM < 0.01
K-562 < 0.01
MOLT-4 < 0.01
SR < 0.01
HL-60 < 0.01
RPMI-8226 0.0251
Non-small cell lung cancer
A549/ATCC < 0.01
HOP-62 < 0.01 - 0.0163
NCI-H460 < 0.01
Colon cancer
HCT-1 16 0.019
CNS cancer
SF-295 < 0.01 - 0.0148
U251 < 0.01 - 0.0168
Melanoma
LOX IMVI < 0.01 - 0.226
Ovarian cancer
OVCAR-8 0.043
Renal cancer
ACHN < 0.01
CAKI-1 < 0.01
SN-12C < 0.01
UO-31 < 0.01 - 0.0234
Prostate cancer
DU-145 0.0149
Breast cancer
MCF-7 < 0.01
GI50 - inhibiting concentration of 50% cellular growth - inteφolated values Range of concentration 0.01 μM - O. l mM
Table 4
In vivo antileukemic activity of BP-1 against P388 murine leukemia in comparison with 5-fluorouracιl and Mitoxantrone
'" Daily dose administered ip for 5 conecutive days b) Data obtained in the Institute of Immunology and Experimental Therapy, Polish
Academy of Sciences, Wroclaw L) Ratio of medium survival time of the treated to the control mice expressed as a percentage. d) Number of toxic deaths/total number of mice 7 days after the day 5 injection as measure of drug toxicity (scheme QD1 -5) e) Cheng C, J. Med. Chem., 22, 502 (1979).
Claims
Claims
1 New derivatives of 6-[(amιnoalkyl)amιno]-7//-benzo[e]peπmιdιn-7-one of
general foπnula 1 , wherein R| stands for hydrogen, methyl, ethyl,
hydroxyethyl group, and R2 is hydrogen, methyl, ethyl, lzopropyl group, and
character n stands for number 2 or 3
2 Process for preparation of new derivatives of 6-[(amιnoalkyl)amιno]-7H-
benzo[e]penmidin-7-one of general foπmila 1 , wherein R| stands for
hydiogen, methv l, ethyl, hv dioxyethyl gioup, and R is hvdrogen, methyl,
ethyl, izoprop l group, and character n stands for number 2 or 3, wherein 5,8-
bιs(benzyloksy)-l ,4-dιamιno-9,10-antracenedιone is heated in
dimethylacetamide with foπnamide in the presence of catalyst, preferably
ammonium metavanadate, at reflux temperature for 20-60 minutes, 6-amιno-
8,1 l -bιs(benz loxy)-7 -benzo[e]peπmιdιn-7-one, isolated from the reaction
mixture, is treated with tπfluoroacetic acid at room temperature, 6-amιno-8,l 1 -
dιhydroxy-7/7-benzo[e]peπmιdιn-7-one, isolated from the reaction mixture, is
heated with aminoalkylamine suitable for the end product, preferably with
addition of N,N,N',N'-tetramethylethylenedιamιne and small amount of water
under neutral gas atmosphere at boiling temperature for 2 - 15 hours, and the
product is isolated and purified, preferably by silica gel column
chromatography, and eventually transfonned into its pharmaceutically
acceptable salt.
Method of treatment of tumor diseases, wherein the diseases are treated with
new derivatives of 6-[(amιnoalkyl)amιno]-7//-benzo[e]peπmιdιn-7-one of
general formula 1 , wherein R stands for hydrogen, methyl, ethyl,
hydroxyethyl group, and R is hydrogen, methyl, ethyl, lzopropyl group, and
character n stands for number 2 or 3
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL96317493A PL188195B1 (en) | 1996-12-12 | 1996-12-12 | Novel derivatives of 6-[aminoalkyl)amino]-7h-benzo[e]perymidin-7-one, method of obtaining them and using them in therapeutic treatment |
| PLP.317493 | 1996-12-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998025910A1 true WO1998025910A1 (en) | 1998-06-18 |
Family
ID=20068820
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL1997/000031 WO1998025910A1 (en) | 1996-12-12 | 1997-12-10 | NEW DERIVATIVES OF 6-[(AMINOALKYL)AMINO]-7H-BENZO[e]-PERIMIDIN-7-ONE, METHOD OF THEIR PREPARATION, AND THEIR USE AS A MEDICAMENT |
Country Status (2)
| Country | Link |
|---|---|
| PL (1) | PL188195B1 (en) |
| WO (1) | WO1998025910A1 (en) |
-
1996
- 1996-12-12 PL PL96317493A patent/PL188195B1/en unknown
-
1997
- 1997-12-10 WO PCT/PL1997/000031 patent/WO1998025910A1/en active Application Filing
Non-Patent Citations (1)
| Title |
|---|
| B.STEFANSKA: "6-(AMINOALKYLAMINO)SUBSTITUTED 7H-BENZO(E)PERIMIDIN-7-ONES AS ANTINEOPLASTIC AGENTS.", JOURNAL OF MEDICINAL CHEMISTRY., vol. 36, 1993, WASHINGTON US, pages 38 - 41, XP002061626 * |
Also Published As
| Publication number | Publication date |
|---|---|
| PL188195B1 (en) | 2004-12-31 |
| PL317493A1 (en) | 1998-06-22 |
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