The present invention relates to new camptothecin analogue compounds having a ketonic E ring with an aminoalkylcarbonyloxy substituent or derivative of said substituent, to a process for their preparation and to pharmaceutical compositions containing them.
Camptothecin (CPT), an alkaloid isolated from Camptotheca accuminata, is an anti-cancer agent having a broad spectrum of activity. Its insoluble nature has for a long time directed research towards the soluble salts of the compound, which have proved to be inactive and toxic.
Another problem comes from the lack of stability of the E ring. In fact, in physiological media, the lactone function of the E ring is in equilibrium with the open hydroxy-acid form. The latter is inactive and seems to have a particular intrinsic toxicity [Cancer Research., 49, 1465 (1989); ibid, 49, 5077 (1989)]. Attempts at modifying this ring in order to make it more stable have been carried out; in particular, the cyclic oxygen atom has been replaced by a nitrogen or sulphur atom, but in each case there is loss of pharmacological activity, so confirming the importance of the lactone [Journal of Medicinal Chemistry, 32, 715 (1989)]. Other structural modifications of the E ring of CPT have been subsequently described, in particular in the patent specification EP 1 101 765. Those newer compounds are characterised by replacement of the lactone by a cyclic ketone function.
The present invention relates to camptothecin analogues having a ketone function on a five-membered E ring and having on that same ring an aminoalkylcarbonyloxy group or a derivative thereof, which substitutes the hydroxyl function alpha to the ketone.
This modification provides the compounds of the invention with enhanced pharmacological activity, especially in respect of their cytotoxicity.
It will accordingly be possible to use them in the manufacture of medicaments for use in the treatment of cancer diseases.
The invention relates to compounds of formula (I):
wherein:
or a 5- to 11-membered bicyclic heterocyclo-alkyl group
An advantageous aspect of the invention relates to compounds of formula (I) wherein Alk represents an ethyl group.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein R80 and R81 together form an oxo group, or wherein R90 and R91 together form an oxo group, or wherein R80 and R81 and also R90 and R91 form two oxo groups. More advantageously, R80 and R81 together form an oxo group and R90 and R91 each represent a hydrogen atom.
Preferred compounds of formula (I) are those wherein R5 represents a hydrogen atom.
Other preferred compounds of formula (I) are those wherein R2, R3 and R4 are selected from a hydrogen atom, a halogen atom, an alkyl group and an alkoxy group.
Other preferred compounds of formula (I) are those wherein R3 and R4 together form a methylenedioxy or ethylenedioxy (preferably methylenedioxy) group.
Advantageous compounds of formula (I) are those wherein R2 represents a hydrogen atom.
An especially advantageous aspect of the invention relates to compounds of formula (I) wherein R1 represents an alkyl, cycloalkyl or cycloalkylalkyl (preferably cycloalkyl) group.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein R1 represents an optionally substituted aryl (preferably phenyl) group.
Another likewise advantageous aspect of the invention relates to compounds of formula (I) wherein G represents an NR6R7 group wherein R6 and R7 form together with the nitrogen atom a 5- to 8-membered (more advantageously 6-membered), monocyclic (advantageously saturated) heterocycloalkyl group:
wherein Y represents a nitrogen atom, an oxygen atom or a CH2 group (more advantageously CH2) and R8 represents a hydrogen atom or an alkyl group (more advantageously hydrogen).
Other preferred compounds are those belonging to the general formula (I) wherein Alk′ represents an alkylene group (more advantageously —CH2—CH2—).
Other preferred compounds of the invention are those wherein X and X′, which are the same or different, represent an oxygen atom or a sulphur atom (more advantageously oxygen).
Especially interesting compounds of the invention are 7-ethyl-2,3-methylenedioxy-13-methyl-8,10-dioxo-8,9,10,12-tetrahydro-7H-cyclopenta-[6,7]indolizino[1,2-b]quinolin-7-yl 3-piperidinopropanoate; 7-ethyl-2,3-methylenedioxy-13-cyclobutyl-8,10-dioxo-8,9,10,12-tetrahydro-7H-cyclopenta[6,7]indolizino[1,2-b]quinolin-7-yl 3-piperidinopropanoate; and 7-ethyl-2,3-methylenedioxy-13-cyclobutyl-8,10-dioxo-8,9,10,12-tetrahydro-7H-cyclo-penta[6,7]indolizino[1,2-b]quinolin-7-yl 3-hexahydrocyclopenta[c]pyrrol-2(1H)-yl-propanoate.
The present invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material a compound of formula (II) synthesised as described in EP 1 101 765:
wherein Alk, R1, R2, R3, R4, R5, R80, R81, R90 and R91 are as defined for formula (I),
wherein the hydroxy group at C7 is converted into X″H wherein X″ represents an SH, amino or alkylamino group to yield the compound of formula (III)
The present invention relates also to the synthesis intermediates (III′):
wherein:
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral or nasal administration, tablets or dragées, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels etc.
The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder and the route of administration, which may be oral, nasal, rectal or parenteral (especially intravenous). The unit dose generally ranges from 0.1 to 500 mg per 24 hours for treatment in from 1 to 3 administrations.
The following Examples illustrate the invention but do not limit it in any way. The structures of the compounds described in the Examples and the Preparations were determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry etc.).
The starting compounds of formulae (II) and (III′) wherein X represents an oxygen atom were synthesised under test conditions described in the patent specification EP 1 101 765 and adapted to the compounds of the invention using prior art documents known to the skilled person. By way of example, Preparations 1 to 6 serve to illustrate, without implying limitation in any way, the manner in which the synthesis described in the patent specification EP 1 101 765 is adapted to the compounds of the invention.
The title compound is prepared according to the method described in Example 11 of the patent specification EP 1 101 765, replacing the 2-bromo-3-bromomethyl-6,7-methylene-dioxyquinoline by 2-bromo-3-bromomethyl-4-methyl-6,7-methylenedioxyquinoline.
The title compound is prepared according to the method described in Example 11 of the patent specification EP 1 101 765, replacing the 2-bromo-3-bromomethyl-6,7-methylene-dioxyquinoleine by 2-bromo-3-bromomethyl-4-cyclobutyl-6,7-methylenedioxyquinoline.
The title compound is prepared according to the method described in Example 11 of the patent specification EP 1 101 765, replacing the 2-bromo-3-bromomethyl-6,7-methylene-dioxyquinoline by 2-bromo-3-bromomethyl-4-piperidinopropyl-6,7-difluoromethylene-dioxyquinoline.
The title compound is prepared according to the method described in Example 11 of the patent specification EP 1 101 765, replacing the 2-bromo-3-bromomethyl-6,7-methylene-dioxyquinoline by 2-bromo-3-bromomethyl-4-cyclobutyl-6,7-difluoromethylenedioxy-quinoline.
The title compound is prepared according to the method described in Example 11 of the patent specification EP 1 101 765, replacing the 2-bromo-3-bromomethyl-6,7-methylene-dioxyquinoline by 2-bromo-3-bromomethyl-4-isopropyl-6,7-difluoromethylenedioxy-quinoline.
The title compound is prepared according to the method described in Example 11 of the ±10 patent specification EP 1 101 765, replacing the 2-bromo-3-bromomethyl-6,7-methylene-dioxyquinoline by 2-bromo-3-bromomethyl-6,7-difluoromethylenedioxyquinoline.
To a suspension of 0.8 g (2 mmol) of the compound of Preparation 1 in 150 ml of dichloromethane there are added, in succession, 1.13 g (7.2 mmol) of 3-piperidin-1-ylpropanoic acid, 2.28 g (12.7 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.34 g (2.78 mmol) of 4-dimethylaminopyridine. The reaction mixture is stirred for 24 hours at ambient temperature and then filtered. The filtrate is washed with sodium bicarbonate solution and then with water and is dried over magnesium sulphate. After concentrating the solvent in vacuo, the residue is dissolved in a solution of dichloromethane containing 30% ethanol. 0.57 ml of 1N hydrochloric acid is added and the precipitate formed is filtered off and recrystallised from acetonitrile to yield the expected compound.
The title compound was synthesised as described in Example 1, replacing the starting material: the compound of Preparation 1 being replaced by that of Preparation 2.
Mass spectrum: (MH+) m/z=570.3
The title compound was synthesised as described in Example 1, replacing the starting material: the compound of Preparation 1 being replaced by that of Preparation 3.
The title compound was synthesised as described in Example 1, replacing the starting material: the compound of Preparation 1 being replaced by that of Preparation 4.
The title compound was synthesised as described in Example 1, replacing the starting material: the compound of Preparation 1 being replaced by that of Preparation 5.
The title compound was synthesised as described in Example 1, replacing the 3-piperidinopropanoic acid by 4-piperidinobutanoic acid and replacing the starting material: the compound of Preparation 1 being replaced by that of Preparation 6.
The compounds of Examples 7 to 21 (see hereinbelow) were obtained by adapting experimental procedures 1 to 6, using suitable substrates.
The title compound was synthesised as described in Example 1, replacing the 3-piperidinopropanoic acid by 3-hexahydrocyclopenta[c]pyrrol-2(1H)-ylpropanoic acid and replacing the starting material: the compound of Preparation 1 being replaced by that of Preparation 2.
The title compound was synthesised as described in Example 1, replacing the 3-piperidin-1-ylpropanoic acid by 3-[(4aR,8aS)-octahydroisoquinolin-2(1H)-yl]propanoic acid and replacing the starting material: the compound of Preparation 1 being replaced by that of Preparation 2.
The title compound was synthesised as described in Example 1, replacing the 3-piperidin-1-ylpropanoic acid by 3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid and replacing the starting material: the compound of Preparation 1 being replaced by that of Preparation 2.
The murine leukaemia L1210 and the human colon carcinomas HCT116 and HT29 were used in vitro. The cells are cultured in RPMI 1640 complete culture medium containing 10% foetal calf serum, 2 mM glutamine, 50 units/ml of penicillin, 50 μg/ml of streptomycin and 10 mM Hepes, pH=7.4. The cells are distributed on microplates and are exposed to the cytotoxic compounds for 4 doubling times, that is to say 48 hours (L1210) or 96 hours (HCT116 and HT29). The number of viable cells is then quantified by a colorimetric assay, the Microculture Tetrazolium Assay (J. Carmichael et al., Cancer Res.; 47, 936-942, (1987)). The results are expressed in terms of the IC50 (the concentration of cytotoxic agent which inhibits proliferation of the treated cells by 50%).
The compounds of the invention appear to be powerful cytotoxic agents, the IC50 values being substantially below 1 μM.
The compounds are formulated in a Tween/water mixture and administered by the intravenous (i.v.) route (administration over three weeks at the rate of once per week, the injection volume being 0.2 ml/mouse with increasing doses of compounds of 6.25, 12.5, 25 and 50 mg/kg) to nude mice (bab/c supplied by Iffa Credo) weighing about 20 g. The maximum tolerated dose (MTD) is the largest dose causing neither death nor a weight loss of more than 20%.
By way of example, the compound of Example 2 has an MTD of 25 mg/kg (intravenous administration once per week for 3 weeks) or two times less toxic than its “non-esterified” close structural homologue (the compound of Preparation 2) for the same in vivo activity with respect to HCT116.
Preparation formula for 1000 tablets each containing 10 mg of active ingredient:
Number | Date | Country | Kind |
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05.08365 | Aug 2005 | FR | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/FR2006/001900 | 8/4/2006 | WO | 00 | 2/5/2008 |