Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-02
2004-01-27
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S510000, C549S511000
Reexamination Certificate
active
06683109
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to derivatives of N-deacetyl-thiocolchicine and 10-deacetyl-baccatin III derivatives of formula (I)
wherein:
n is an integer of 0 to 8;
R is a residue of formula a), b), c), d) or e):
wherein:
R
1
and R
2
, which can be the same or different, are hydrogen or a group of formula:
n is preferably an integer of 1 to 7, more preferably 1.
TECHNICAL FIELD
Colchicines and thiocolchicines are known antiblastic compounds capable of destabilizing microtubules through interaction with tubulin
Colchicine is currently used in the therapy of gout and related inflammatory conditions, but its use is restricted to the acute phases due to its high gastro-intestinal toxicity.
A number of colchicine or thiocolchicine derivatives have been studied, in view of a possible use thereof as antitumor medicaments, but the efforts of researchers have to date been unsuccessful due to the often very restricted therapeutical index of such compounds.
Only one colchicine derivative, demecolcine, has been used in the past in clinic for the treatment of leukemias, but with poor success.
The antiproliferative activity of taxane derivatives (paclitaxel and derivatives) is related to the capability of irreversibly binding to the alpha and beta forms of tubulin in the microtubule as well. The oxethane and the phenyl groups on the isoserine side chain proved to be essential as regards activity: baccatine in fact, lacking the isoserine chain, has substantially no antiproliferative activity, contrary to paclitaxel and other C
13
esters of isoserine, which can form bonds with two different sites of the microtubule preventing depolymerization hence arresting the activity of the mitotic spindle.
SUMMARY OF THE INVENTION
It has now surprisingly been found that compounds of formula (I) have anti-proliferative activity, although lacking affinity to tubulin, both in the microtubules assembling and disassembling steps.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The activity of the compounds of formula (I) is therefore due to an unexpected action mechanism that cannot be evinced from the present knowledge in the anti-tubuline drug field.
The compounds of the invention have powerful antimitotic activity and are characterized by favorable therapeutic index which makes them suitable for the therapeutical treatment of various forms of tumors, as well as for degenerative rheumatoid arthritis, a disease characterized by excessive proliferation and abnormal migration of leukocytes.
Compounds (I) have cytotoxicity comparable to that of the most effective antitumor medicaments, while having a remarkably wider action spectrum, particularly against cells resistant to known drugs.
Compounds (I) are prepared by reacting N-deacetyl-thiocolchicine with dicarboxylic acid reactive derivatives in dry solvents in such conditions as to obtain a N-monoacylation product which is subsequently reacted with the baccatine III derivative, optionally protected at the 7, 13 or 10 positions, depending on the desired compound, in the presence of a suitable condensing agent, such as dicyclohexylcarbodiimide. Any protective groups optionally present are removed and/or the hydroxy groups on the baccatine III residue are selectively acylated to directly yield compounds (I).
When in compounds (I) R is a group of formula c), thanks to the reactivity of the hydroxy group in the isoserine chain, the reaction can be carried out without previously protecting the other hydroxy groups present on the taxane compound.
Examples of suitable dicarboxylic acid reactive derivatives comprise acyl halides, acid chlorides, reactive anhydrides or esters.
Alternatively, a taxane derivative can also be acylated with a dicarboxylic acid and the resulting product be condensed with N-deacetyl-thiocolchicine.
The compounds of the invention are useful in the treatment of proliferative pathologies and in particular tumors of various origins, rheumatoid arthritis or other degenerative pathologies wherein antiproliferative and anti-inflammatory actions are indicated.
For this purpose, compounds (I) will be administered in the form of pharmaceutical compositions suitable to the oral, parenteral, epicutaneous or transdermal administrations. The dosage of compounds (I) will range from 1 to 100 mg/m
2
body area, depending on the administration route. The compounds will preferably be administered orally.
Examples of compositions comprise capsules, tablets, vials, creams, solutions, granulates.
The following examples illustrate the invention in greater detail.
REFERENCES:
patent: 5426224 (1995-06-01), Lee et al.
patent: WO 93/02105 (1993-02-01), None
patent: WO 93/11120 (1993-06-01), None
patent: WO 97/24459 (1997-07-01), None
S.-X Zhang et al., “Antitumor Agents. 199. Three-Dimensional Quantitative Structure --Activity Relationship Study of the Colchicine Binding Site Ligands Using Comparative Molecular Field Analysis,” J. Med. Chem. 2000, 43:2, pp. 167-176, 2000.
Bombardelli Ezio
Pontiroli Alessandro
Indena S.p.A.
Pennie & Edmonds LLP
Trinh Ba K.
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