Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-08-02
2003-09-30
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S047000, C564S057000, C514S595000, C514S616000
Reexamination Certificate
active
06627774
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to derivatives of N-deacetyl-thiocolchicine or of the isoster thereof of formula (I)
wherein:
n is an integer from 0 to 8;
Y is a CH
2
group or, when n is 1, can also be a group of formula NH.
TECHNICAL FIELD
Colchicines and thiocolehicines are known antiblastic compounds capable of destabilizing microtubules through interaction with tubulin.
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.
SUMMARY OF THE INVENTION
It has now been found that compounds of formula (I) have anti-proliferative activity, in particular on cells expressing MDR (multi-drug resistance) phenotype with an approximately 1:1 ratio of activity on sensitive cells to activity on resistant cells.
The compounds of the invention have in fact 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.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Compounds (I) wherein Y is CH
2
are prepared by reacting N-deacetyl-thiocolchicine with dicarboxylic acid reactive derivatives in dry solvents. Examples of suitable dicarboxylic acid reactive derivatives comprise chlorides, reactive anhydrides or esters, in particular, N-hydroxysuccinyl diesters obtainable by reacting said acids with N-hydroxy-succinimide. The reaction is preferably carried out in solvents such as diethyl ether, dioxane or tetrahydrofuran in the presence of bases, for example triethyamine.
Compounds (I) wherein Y is CH
2
are prepared by reacting N-deacetyl-thiocolchicine with dicarboxylic acid reactive derivatives in dry solvents. Examples of suitable dicarboxylic acid reactive derivatives comprise chlorides, reactive anhydrides or esters, in particular N-hydroxysuccinyl diesters obtainable by reacting said acids with N-hydroxy-succinimide. The reaction is preferably carried out in solvents such as ethyl ether, dioxane or tetrahydrofuran in the presence of bases, for example triethylamine.
On the other hand, compounds (I) wherein Y is NH and n is 1 can be prepared by reacting N-deacetyl-thiocolchicine with N-hydroxy-succinimide in the presence of amines and condensing agents such as dicyclohexylcarbodiimide (DCC), in a suitable aprotic solvent, preferably a chlorinated hydrocarbon (methylene chloride, chloroform). Said compounds can also be obtained as side-products from the reaction between dicarboxylic acid N-hydroxysuccinyldiesters and N-deacetyl-thiocolchicine.
The activity of these compounds was evaluated on a wide number of resistant tumour cells expressing the MDR phenotype; these compounds proved to be particularly active on different sensitive colon lines expressing MDR.
The following Table reports by way of example the activity of these two compounds, comparing their biological activity to thiocolchicine and taxol as reference molecules.
TABLE
IC
50
nM
Compounds
MCF7
MCF7-ADRr
MCF7-ADRr/MCF7
Tiocol 39 (Ex. 1)
12
43
3.58
Tiocol 43 (Ex. 4)
21
36
1.71
Tiocol 54 (Ex. 2)
2.6
2.8
1.07
Thiocolchicine
0.02
400
20000
The cytotoxic activity was evaluated according to M. C. Alley et al.,
Cancer Research,
48, 589-601, 1998.
The above-reported data evidence the high cytotoxic activity of the compounds of the invention on both sensitive cell lines and different drug-resistant cell lines to various antitumor drugs.
The compounds of the invention are therefore 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: 4533675 (1985-08-01), Brossi et al.
patent: 5667764 (1997-09-01), Kopia et al.
patent: WO 97/01570 (1997-01-01), None
patent: WO 97/47577 (1997-12-01), None
M.L. Gelmi et al., “N-Deacetyl-N-aminoacylcolchicine derivatives: synthesis and biological evaluation on MDR-negative human cancer cell lines, ” J. Med. Chem. 42:25, pp. 5272-5276, Nov. 25, 1999.
Q. Shi et al., “Antitumor agents. 172. Synthesis and biological evaluation of novel deacetamidothiocolchicin-7-ols and ester analogues as antitubulin angents, ” J. Med. Chem. 40:6, pp. 961-966, Mar. 14, 1997.
Bombardelli Ezio
Pontiroli Alessandro
Indena S.p.A.
Kumar Shailendra
Pennie & Edmonds LLP
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