Ureido and thioureido derivatives of 4-amino-2(5H)-furanones...

Details Ureido and thioureido derivatives of 4-amino-2(5H)-furanones... Ureido and thioureido derivatives of 4-amino-2(5H)-furanones...

2000-06-02

2001-12-25

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...

C514S447000, C514S472000, C514S473000, C549S063000, C549S066000, C549S321000, C549S323000

Reexamination Certificate

active

06333346

ABSTRACT:

The present invention relates to ureido and thioureido derivatives of 4-amino-2(5H)-furanones and 4-amino-2(5H)-thiophenones which were found to possess a marked antitumor activity, especially against colon cancers.
BACKGROUND OF THE INVENTION
Colo-rectal carcinoma is one of the most common tumors in industrialized world; with an incidence of approximately 421,000 new cases/year world-wide, it is second only to lung and mammary tumors in causing death. The rate of patients curable with surgery only is approximately 45-50%. The others may be treated with combination chemotherapy which allows to a complete remission rate of no more than 5%.
Colo-rectal tumors are usually refractory or poorly sensitive to available chemotherapy and the only agent which provides some responses against this cancer is 5-Fluorouracil.
So far no therapeutic alternatives exist after the failure of the first-line combination chemotherapy essentially based on 5-FU.
Despite many new investigational agents are undergoing preclinical and clinical studies against colorectal cancer, it is generally believed that only compounds with innovative structures and possible new mechanisms of action may be successful against this highly refractory tumor hystotype.
Therefore the search for new active drugs in this indication still represents one of the most interesting and attractive field in oncology.
We have now discovered a new class of compounds, namely 4-ureido and thioureido 2(5H)-furanones, respectively 2(5H)-thiophenones, which possesses a marked antitumor activity, especially against colon cancers.
Phenylureido furanones have been already described having activity as defoliants (Reissue U.S. Patent 27,894), as herbicides (JP 63-174983) or in Bull.Chem.Soc.Jpn. Vol. 60, 2139ff as intermediates. However, no pharmaceutical activity, especially antitumour activity, has been reported in these documents. Only DE-A-25 16 555 describes 1-tert.alkyl-3-(substituted furyl)-urea-derivatives with an antihypertensive activity.
DESCRIPTION OF THE INVENTION
Object of the present invention are compounds of the general formula (I):
wherein:
A is oxygen or sulfur;
X is oxygen or sulfur;
R1 and R2 are independently hydrogen or an alkyl group woth from 1 to 6 carbon atoms;
R is selected from: (C
1
-C
10
)alkyl, (C
3
-C
7
)cycloalkyl, naphthyl, phenyl, phenyl substituted by from 1 to 3 groups selected from: (C
1
-C
4
)alkylthio, (C
1
-C
4
)alkylsulphinyl, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)hydroxyalkyl, (C
1
-C
4
); chlorine, bromine, iodine or fluorine; (C
1
-C
4
)perfluoroalkyl; hydroxy; (C
1
-C
4
)alkoxy; amino; mono- or di-(C
1
-C
4
)alkylamino; aminosulphonyl; (C
1
-C
4
)alkylsulphonamido; phenyl- or tolyl-sulphonoamido; carboxy; (C
1
-C
4
)alkoxycarbonyl; amidocarbonyl or (C
1
-C
4
)alkylamidocarbonyl; carboxaldehyde; (C
1
-C
4
)alkylcarbonyl; nitro; phenylthio; cyanomethyl, and optionally substituted phenyloxy or optionally substituted phenyl-(C
1
-C
4
)-alkyl or R is a 5- or 6-membered aromatic or non-aromatic heterocycle containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which can be optionally benzocondensed, with the proviso, that when A is oxygen and X is oxygen, R is not (C
1
-C
10
) alkyl.
the pure stereoisomers or mixtures thereof as well as salts thereof with pharmaceutically acceptable acids or bases, for the use as medicaments, in particular as antitumor agents. When R is a heterocycle, it is preferably selected from pyridine, pyrrole, thiazole, thiophene, furane, imidazole, pyrazine, pyrimidine, quinoline, isoquinoline, indole, 3,4-methylenedioxyphenyl, piperazine, piperidine, morpholine and pyrrolidine.
The compounds in which R is an unsubstituted phenyl group or (C
1
-C
10
) alkyl and X is oxygen are known (US-Re 27,894; JP 63-174983; DE-A-2 516 555 and Bull.Chem.Soc.Jpn. Vol. 60, 2139ff). Therefore, another object of the present invention are new compounds of formula (I), with the proviso that, when X is oxygen, R is not an unsubstituted phenyl group or C
1
-C
10
(alkyl).
Preferred compounds of formula (I) are those in which X is oxygen, R1 and R2 are hydrogen and R is a substituted phenyl group.
Particularly preferred compounds of formula (I) are:
4-[N-(4-chlorophenyl)aminocarbonylamino]-2(5H)-furanone;
4-[N-(4-ethyl-3-chlorophenyl)aminocarbonylamino]-2(5H)-furanone.
A further object of the present invention is to provide processes for the preparation of the compounds of formula (I).
A still another object of the present invention are pharmaceutical formulations containing a pharmaceutically effective dosage of one or more compounds of formula (I) in admixture with pharmaceutically acceptable excipients.
PREPARATION OF THE COMPOUNDS OF THE INVENTION
The compounds of formula (I) wherein A is oxygen, can be prepared by reacting bromo- or chloro-acetoacetate of formula (II):
wherein R1 and R2 have the above meanings, H
2
l is bromine or chlorine and Y is a lower alkyl group, with an urea or thiourea of formula (III)
wherein R and X have the above meanings, preferably in a solvent and at temperatures ranging from room temperature to the boiling temperature of the solvent, as described in US-Re 27,894, which is herein incorporated by reference.
The preparation of intermediates of formula (II) and (III), which are mainly commercial and widely known products, is also described in US-Re 27,894.
An alternative process comprises the reaction of a 4-amino-2(5H)furanone of formula (IV):
wherein A is oxygen or sulfur and R
1
and R
2
have the above-mentioned meanings, with an isocyanate or an isothiocyanate of formula (V):
R−N=C=X
  (V)
as described in JP 63-174983, which is herein incorporated by reference. The reaction comprises the formation of a sodium salt of intermediate of formula (IV) (by reaction with sodium hydride at 40-50° C.), followed by the condensation reaction with the compound of formula (V) at about 50° C. The use, in the first step, of a different strong base at temperatures ranging from 0° C. to 100° C. can be also advantageously provided.
A still alternative process is to react intermediates of formula (IV) with 1,1′-carbonyl diimidazole or 1,1′-thiocarbonyl diimidazole, respectively, followed by reaction with an amine of formula (VI) R—NH
2
.
Another alternative process is to react a compound of formula (VII):
wherein A is oxygen or sulfur and R
1
and R
2
have the above-mentioned meanings, with an urea or thiourea of formula (III), in solution at reflux or at 50 to 150° C., preferably at 80 to 120° C., without solvent and, if necessary to achieve a clear melt, a small amount of a high boiling solvent e.g. toluene, xylene, dioxane, dimethylformamide, nitromethane or n-butanol.
The synthesis of the 4-aminofuranones of formula (IV) is described in Bull. Chem. Soc. Jpn.,
60
, 2139-50 (1987), which is herein incorporated by reference. When R1 and R2 are both hydrogen, the compound of formula (IV) can be obtained by fusion of the corresponding compound of formula (VII) with ammonium acetate.
The compounds of formula (V) and (VI) are commercial and known compounds, which can be prepared according to methods which are part of the general knowledge of the chemist.
The compounds of formula (VII) can be prepared by heating the halogen-acetoacetates of formula (II) in a solvent.
BIOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION
The compounds of the invention were tested against three human colon tumor cell lines (HT 29, HCT 116 and LoVo). After 144 hours of incubation of the cells with the compound to be tested, the cytotoxicity is evaluated using the MTT assay (Mosman, T. “Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay”; J. Immunol. Methods, (1983),
65
, 66; Green, L. M., “Rapid Colorimetric Assay for Cell Viability; Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines”, J. Immunol. Methods, (1984),
70
, 257-268). The results are expressed as IC
50
(Tg/ml), that it the concentration of the tested compound which

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