Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-11-24
2000-06-27
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514546, 514548, 514680, 544 99, 560194, 560255, 568 43, 568326, A61K 3112, A61K 31536, C07C 49755, C07D26534
Patent
active
060807393
DESCRIPTION:
BRIEF SUMMARY
TECHNOLOGICAL BACKGROUND
The present invention relates to novel colchicine derivatives having antiproliferative, antineoplastic and antiinflammatory activities, the methods for the preparation thereof and the pharmaceutical formulations containing them.
Colchicine is a known pseudo-alkaloid widely used for a very long time in therapy for the treatment of gout, a pathology on which it acts very quickly and specifically, even though it should be used for short times due to its toxicity. A colchicine derivative, namely thiocolchicoside, is widely used to treat contractures and in inflammatory conditions on skeletal muscles. In addition, colchicine is a very potent antiblastic agent, which acts blocking the formation of the mitotic spindle during cell division; this latter aspect has been investigated thoroughly for any antineoplastic activity and a great deal of colchicine derivatives have been prepared to this purpose. Colchicine as such and a number of its derivatives could not be used clinically due to their high toxicity, and therefore their unacceptable risk/benefit ratio. Only one colchicine derivative, demecoicine, is used in some degree in oncology for the treatment of some leukemia forms.
Therefore the problem exist of the availability of antineoplastic medicaments having a satisfactory risk/benefit ratio, i.e. a high therapeutical activity with poor or no side-effects.
Another problem in the antineoplastic field is the resistance to the medicament which takes place in specific phenotypes.
Now it has surprisingly been found that some colchicine derivatives have a high cytotoxic activity both on the normal cancerous cells and on the corresponding resistant phenotype (MDR).
The compounds of the invention are potent apoptosis inducers, proving to be markedly better than the compounds of the prior art. Due to their lipophilic, characteristics, the compounds are particularly bioavailable after oral administration. Moreover, the compounds of the present invention can be administered by the parenteral or topical routes as well.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula (I) ##STR1## wherein R is a methoxy or methylthio group and R.sub.1 is a straight or branched alkyl or alkenyl group having 1 to 6 carbon atoms, or an alicyclic or heterocyclic moiety, a saturated or unsaturated mono or dicarboxylic or amino acidic acyl residue or a .beta.-D-glucose or 6-deoxygalactose residue.
Examples of alkyl group are methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, t-butyl, pentyl, neopentyl, hexyl.
Examples of alkenyl group are propenyl, 1-butenyl, 2-butenyl, 1-pentenyl.
Examples of alicyclic group are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Examples of heterocyclic group are benzotriazolyl, methyltetrazolyl.
Examples of acyl residue are ximenoyl, succinyl, aspartyl.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula I are prepared starting from the natural compounds colchicine or thiocolchicine or from the C3-derivatives thereof commercially available or obtainable with methods known in literature. As described in literature, the C3 derivatives can be prepared by reacting the 3-O-dimethyl derivative with an alkyl or acyl halide. The hydrolysis of said compounds with strong mineral acid aqueous solutions allows to obtain selectively, changing the temperature and the reaction time, the corresponding N-deacetyl derivatives. In particular, the deacetylation of thiocolchicine or of the C3 derivatives thereof can be carried out by subjecting the compounds to acidic hydrolysis; in the case of thiocolchicine, the hydrolysis with halo acids or, more preferably, with sulfuric acid (20% H.sub.2 SO.sub.4 --120 h), allows one to obtain N-deacetylthiocolchicine and 3-demethyl-N-deacetylthiocolchicine in nearly quantitative yields.
The N-deacetyl derivatives are reacted with 4-formyl-1-methylpyridinium-p-toluenesulfonate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to prepare the compounds of formula I.
Alternatively, reacting the N-deacetyl derivatives with 2,3-d
REFERENCES:
patent: 3442953 (1969-05-01), Muller et al.
patent: 4349548 (1982-09-01), Jones
Al-Tel et al., "New Natural Colchicinoids: Indications of Two Possible Catabolic Routes for the Colchicine Alkaloids", J. Nat. Prod., vol. 53, No. 33, 623-629 (1990).
Banwell et al., "Semisyntheses, X-Ray Crystal Structures and Tubulin-Binding Properties of 7-Oxodeacetamidocolchicine and 7-Oxodeacetamidoisocolichicine", Aust. J. Chem., vol. 45, 1577-1588 (1992).
Shi et al., "Antitumor Agents. 172. Synthesis and Biological Evaluation of Novel Deacetamidothiocolchicin-7-ols and Ester Analogs as Antitubulin Agents", J. Med. Chem., vol. 40, 961-966 (1997).
Indena S.p.A.
Raymond Richard L.
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