EP0980372A2 - COMPOSES CYTOTOXIQUES: DERIVES DU SYSTEME CYCLIQUE PYRIDO 2,3,4-$i(kl)] ACRIDINE - Google Patents
COMPOSES CYTOTOXIQUES: DERIVES DU SYSTEME CYCLIQUE PYRIDO 2,3,4-$i(kl)] ACRIDINEInfo
- Publication number
- EP0980372A2 EP0980372A2 EP98919330A EP98919330A EP0980372A2 EP 0980372 A2 EP0980372 A2 EP 0980372A2 EP 98919330 A EP98919330 A EP 98919330A EP 98919330 A EP98919330 A EP 98919330A EP 0980372 A2 EP0980372 A2 EP 0980372A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- group
- compound according
- groups
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a series of new polycyclic aromatic alkaloids having a pyrido[2,3,4-&,/]acridine skeleton which have cytotoxic properties and which can therefore be used in the treatment of malignant tumours.
- the invention also provides methods and compositions using these new compounds as well as processes for their preparation.
- the polycyclic aromatic alkaloids based on the pyrido[2,3,4-£,/]acridine skeleton are a growing class of ascidian metabolites that often exhibit a variety of interesting biological properties, including antitumour activity.
- This class of compounds comprises three main structural types, depending of the position of the fusion between the parent structure and additional rings present in the natural product.
- cystoditines ⁇ have the base skeleton mentioned above, while amphimedine, ⁇ meridine ⁇ and cystodamine ⁇ bear an additional pyridine ring attached to the h bond; ascididemin, ⁇ its derivatives, ⁇ the kuanoniamines ⁇ and shermilamine A 9 show this additional ring at the face, and eilatine at both.10
- Our target compounds can be regarded as regioisomers both of meridine and amphimedine, but they have not been so far isolated from natural sources.
- X is selected from the group consisting of O, and NR 3 , where R 3 represents a lower alkyl group;
- Y is selected from the group consisting of CH and N;
- R 1 and R 2 are independently selected from the group consisting of NH 2 , NHR 4 and NR 5 2 , where R and R 5 each represent a lower alkyl group, or R 1 and R 2 together represent a cycle selected from (a), (b) and (c):
- R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen atoms, lower alkyl groups, hydroxy groups and lower alkoxy groups;
- Z is selected from the group consisting of O and NH; and pharmaceutically acceptable salts thereof.
- the lower alkyl groups and the lower alkyl moiety of the lower alkoxy groups are straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl groups.
- R 6 and R 7 are preferably independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms; more preferably, R and R are independently selected from the group consisting of hydrogen atoms, methyl groups and ethyl groups; and, most preferably, R 6 represents a methyl group and R 7 represents a hydrogen atom.
- Z represents a group of formula NH.
- R , R and R are preferably selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, hydroxy groups and ft 7 Jt alkoxy groups having from 1 to 4 carbon atoms; more preferably, R , R and R are independently selected from the group consisting of hydrogen atoms, methyl groups, ethyl groups and hydroxy groups; and, most preferably, R 6 represents a hydroxy group and R 7 and R each represent a hydrogen atom.
- the present invention relates to novel synthetic compounds of general structure (II) or (III):
- R 6 , R 7 and R 8 are as defined above.
- the present invention also provides a method for treating a mammal affected by a malignant tumor sensitive to a compound having the general formula (I), which comprises administering to the affected individual a therapeutically effective amount of the compound having the general formula (I) or a pharmaceutical composition thereof.
- the present invention further provides pharmaceutical compositions, particularly useful in the treatment of malignant tumors, which contain as the active ingredient a compound having the general formula (I), as well as a process for the preparation of said compositions.
- a further aspect of the present invention provides a method for preparing the compounds of general formula (I) and, in particular, Compounds Nos. IB-96213 and IB-98205.
- the compounds of the present invention are cytotoxic, compounds such as IB-96213 and IB- 98205 exhibiting antitumor activity, especially against cell lines derived from human solid tumors, such as human lung carcinoma, human colon carcinoma and human melanoma, and, the like. They are also active against other tumor cell lines, like leukemia and lymphoma.
- Compounds of formula (I), such as IB-96213 and IB-98205, have in vitro antitumor selectivity for solid tumors.
- compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) dosage form, with suitable formulation of oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.
- a pharmaceutical composition comprising compounds with formula (I), will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and tumor being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
- the invention is further illustrated by the following Examples, which demonstrate the preparation of various of the compounds of the present invention.
- the reagents used were of commercial origin (Aldrich, Fluka) and were employed without further purification.
- Solvents (SDS, Scharlau) were purified and dried by standard procedures. Reactions were monitored by thin-layer chromatography, using Scharlau and Macherey-Nagel plates with fluorescent indicator. Separations by flash liquid chromatography were performed using silica gel SDS 60 ACC (230-400 mesh).
- Step 1(a) 4-(o-Trifluoroacetamidophenyl)-l-dimethylamino-l-azadiene (Formula lb) Method A
- Trifluoroacetic anhydride (1.39 g, 6.63 mmol) was added dropwise to a stirred solution of 4-( ⁇ -aminophenyl)-l-dimethylamino-l -azadiene (2) 12 (837 mg, 4.42 mmol) in dry ethyl ether (10 ml). The solution was stirred at room temperature for 15 min and evaporated under reduced pressure at room temperature. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give the title compound lb; yield, 1.023 g (88 %).
- Method B a) o-(trifluoroacetamido)benzaldehyde (4).
- o-nitrobenzaldehyde 3 g, 19.86 mmol
- 35 % aqueous hydrochloric acid 35 ml
- 21 g (93.1 mmol) of tin (II) chloride 21 g (93.1 mmol) of tin (II) chloride in small portions.
- the suspension was stirred at room temperature for 72 h, neutralized with 6N aqueous sodium hydroxide and extracted with chloroform (4 x 50 ml).
- chloroform layers were dried over sodium sulphate and evaporated, yielding 1.87 g (78 %) of o-aminobenzaldehyde 3.
- the compounds of formula (I) of the present invention show good antitumor activity.
- IB-96213 and IB-98205 display good antitumor activity against several mammalian cancer cell lines. Its antitumor activity has been detected in vitro by culturing the tumor cells following the methodology described by Bergeron et al. 16 , and by Schroeder et al . Activity against different mmors as mouse lymphoma, human NSC lung carcinoma, human melanoma and human colon carcinoma has been observed.
- NSC lung carcinoma and melanoma cells were 100 times more sensitive than mouse lymphoma and 1000 times more sensitive than human colon carcinoma cells.
- Biological activity Cells were maintained in logarithmic phase of growth in Eagle's Minimum Essential Medium, with Earle's Balanced Salts, with 2.0 mM L-glutamine, with non- essential amino acids, without sodium bicarbonate (EMEM/neaa); suplemented with 10% Fetal Calf Serum (FCS), 10 "2 M sodium bicarbonate and 0,1 g/1 penicillin-G + streptomycin sulfate.
- EMEM/neaa Eagle's Minimum Essential Medium, with Earle's Balanced Salts, with 2.0 mM L-glutamine, with non- essential amino acids, without sodium bicarbonate (EMEM/neaa); suplemented with 10% Fetal Calf Serum (FCS), 10 "2 M sodium bicarbonate and 0,1 g/1 penicillin-G + streptomycin sulfate.
- FCS Fetal Calf Serum
- the tumor cell lines employed have been P-388 (ATCC CCL-46, suspension culture of a lymphoid neoplasm from DBA/2 mouse), A-549 (ATCC CCL-185, monolayer culture of a human lung carcinoma), HT-29 (ATCC HTB-38, monolayer culture of a human colon carcinoma) and MEL-28 (ATCC HTB-38, monolayer culture of a human melanoma).
- P-388 cells were seeded into 16 mm wells at 1x10 cells per well in 1 ml aliquots of MEM 5FCS containing the indicated concentration of drug. A separate set of cultures without drug was seeded as control growth to ensure that cells remained in exponential phase of growth. All determinations were carried out in duplicate. After three days of incubation at 37°C, 10% CO 2 in a 98% humide atmosphere, an aproximate IC 50 was determined by comparing the growth in wells with drug to the growth in wells control.
- A-549, HT-29 and MEL-28 were seeded into 16 mm wells at 2xl0 4 cells per well in 1 ml aliquots of MEM 10FCS containing the indicated concentration of drug. A separate set of cultures without drug was seeded as control growth to ensure that cells remained in exponential phase of growth. All determinations were carried out in duplicate. After three days of incubation at 37°C, 10% CO 2 in a 98% humide atmosphere, the wells were stained with 0.1 %
- Crystal Violet An aproximate IC 50 was determined by comparing the growth in wells with drug to the growth in wells control.
- the quinones used as dienophiles were prepared from 2,5- dimethoxyaniline using previously published procedures: a) C. Avendano, E. de la Cuesta, C. Gesto, Synthesis, 1991, 727. b) M. M. Blanco, C. Avendano, N. Cabezas, J. C. Menendez, Heterocycles, 1993, 36, 1387. c) M. A. Alonso, M. M. Blanco, C.
Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9708751.4A GB9708751D0 (en) | 1997-04-29 | 1997-04-29 | New cytotoxic analogues of marine natural products derivatives of the pyrido (2,3,4-K1) acridine ring systems |
GB9708751 | 1997-04-29 | ||
PCT/GB1998/001239 WO1998049165A1 (fr) | 1997-04-29 | 1998-04-29 | COMPOSES CYTOTOXIQUES: DERIVES DU SYSTEME CYCLIQUE PYRIDO[2,3,4-kl] ACRIDINE |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0980372A2 true EP0980372A2 (fr) | 2000-02-23 |
Family
ID=10811575
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98919330A Withdrawn EP0980372A2 (fr) | 1997-04-29 | 1998-04-29 | COMPOSES CYTOTOXIQUES: DERIVES DU SYSTEME CYCLIQUE PYRIDO 2,3,4-$i(kl)] ACRIDINE |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0980372A2 (fr) |
JP (1) | JP2001522370A (fr) |
AU (1) | AU7220898A (fr) |
CA (1) | CA2287862A1 (fr) |
GB (1) | GB9708751D0 (fr) |
WO (1) | WO1998049165A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2790954B1 (fr) | 1999-03-18 | 2003-08-08 | Lafon Labor | Composition pharmaceutique a base de composes polyaromatiques |
GB9918079D0 (en) * | 1999-07-30 | 1999-10-06 | Univ Barcelona | New cytotoxic pyrido (2,3,4-kl) acridine derivatives |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5182287A (en) * | 1989-11-03 | 1993-01-26 | Harbor Branch Oceanographic | Bioactive heterocycle alkaloids and methods of use |
-
1997
- 1997-04-29 GB GBGB9708751.4A patent/GB9708751D0/en active Pending
-
1998
- 1998-04-29 WO PCT/GB1998/001239 patent/WO1998049165A1/fr not_active Application Discontinuation
- 1998-04-29 CA CA002287862A patent/CA2287862A1/fr not_active Abandoned
- 1998-04-29 JP JP54674598A patent/JP2001522370A/ja not_active Ceased
- 1998-04-29 AU AU72208/98A patent/AU7220898A/en not_active Abandoned
- 1998-04-29 EP EP98919330A patent/EP0980372A2/fr not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO9849165A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1998049165A1 (fr) | 1998-11-05 |
GB9708751D0 (en) | 1997-06-25 |
AU7220898A (en) | 1998-11-24 |
JP2001522370A (ja) | 2001-11-13 |
CA2287862A1 (fr) | 1998-11-05 |
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