ITMI990456A1 - HETEROCYCLIC COMPOUNDS WITH ANTI-TUMOR ACTIVITY - Google Patents

Description

Description of the industrial invention entitled:

"HETEROCYCLIC COMPOUNDS WITH ANTI-TUMOR ACTIVITY"

The present invention relates to heterocyclic compounds having antitumor activity, in particular against solid tumors, especially colon tumors.

Colorectal cancer is one of the most common cancers in the industrialized world as it has an incidence of about 421,000 new cases a year worldwide and is second only to lung and breast cancers as a cause of death.

The percentage of surgically curable patients is approximately 45-50% and the remaining patients can be treated with combination chemotherapy, achieving a complete remission rate of no more than 5%.

Colorectal tumors are usually refractory or insensitive to currently available chemotherapy and the only agent that provides a certain response against this type of cancer is 5-fluorouracil.

Unfortunately, there are currently no therapeutic alternatives in the event of failure of combinatorial attack chemotherapy based essentially on 5-FU.

Therefore, the need is particularly felt to have available new drugs active against this type of cancer.

Patent application EP 997115391.1 describes a new class of compounds with antitumor activity particularly against colon tumors. These compounds are 4-ureido and 2 (5H) -furanone or 2 (5H) -thiophenone thioureido derivatives.

The present invention relates to new heterocyclic compounds endowed with antitumor activity in particular against colon tumors having the following general formula (I)

in which:

- Y is oxygen, sulfur or NH;

- n is 0 or 1

- R1 is selected from the group consisting of hydrogen,

they are hydrogen, C1-10alkyl, or Ra

and Rb together with the nitrogen atom to which they are linked form a heterocyclic ring with 4-7 members; Rc is hydrogen, alkyl or alkali or alkaline earth metal;

R is C3-7 cycloalkyl, C7-14arylalkyl, naphthyl, phenyl optionally mono or polysubstituted, 5 or 6 membered aromatic or non-aromatic heterocyclic ring optionally benzocondensate;

R2 is hydrogen or C1-6alkyl;

the dashed line indicates an optional link;

their pure or mixed stereoisomers and their salts with pharmaceutically acceptable acids or bases, with the conditions that:

when and the dashed line indicates a bond, R is different from phenyl or mono or polysubstituted phenyl; when and the dashed line indicates a bond, R is different from -NH-CO-NH-;

when

when it is different from a 5-membered aromatic heterocyclic ring containing one nitrogen atom and one sulfur atom,

for use as medicaments.

In Chem.Abstracts, Vol. 72, 1970, page 311, 31597r and in US patent 3 472 878, N- (hydroxyaryl) aconamides with antibacterial activity, of formula

In US patent 3 496 187 N-heterocyclic aconamide derivatives of formula are described

as antibacterials and amoebicides.

Jpn. J. Cancer Res. (1997), 88 (9), 815-820, describes 5-hydroxy-4- [2-phenyl- (E) -ethenyl] -2 (5H) -furarone as a chemoprotective agent against carcinogenesis in the colon.

The present invention also relates to new compounds of formula (I) with the further conditions that:

when and the dashed line indicates a bond, R is different from phenyl and monosubstituted phenyl;

when and the dashed line indicates a bond, R is different from methyl, phenyl or benzyl; when and the dashed line indicates a bond, R is different from 2,3,6-trimethylphenyl;

when and the dashed line indicates a bond, R is different from methyl;

when and the dashed line indicates a bond, R is different from phenyl and p-nitrophenyl;

The previous exclusions take into account some known heterocyclic derivatives, not endowed with pharmacological activity, described in the following publications.

In Chem. Abstracts Vol. 81, 1974, page 3790, 3796x, Narylaconamides are described as intermediates in the preparation of furoquinolines. The aryl group consists of phenyl possibly substituted by one or two methoxy groups.

Amino-substituted furanone derivatives of formula

are described in Heterocycles (1988), 27 (8), 1907-23.

Patent DE 2 108 926 describes the preparation of the 3-acetyl-4-hydroxy-2-butenoic acid lactone.

By Arch. Pharm. (Weinheim) 320, 749-755 (1987) the following compounds are known: 4- (4-nitrophenylhydrazido) -2 (5H) -furanone and 4-phenylhydrazido-2 (5H) -furanone.

N-acyl derivatives of 4-aminofuranones according to the following formula

are known from Bull. Chem. Soc. Jpn., 60, 2139-2150 (1987), as intermediates in the synthesis of basidalin, an antitumor antibiotic.

J. Chem. Res., Synop. (1987), (4), 118-19, describes furanone derivative of formula

as products of thermolysis of 6-beta-hydroxyplysistatin.

When R is a heterocyclic ring, it is preferably selected from the group consisting of pyridine, pyrrole, thiazole, thiophene, furan, imidazole, pyrazine, pyrimidine, quinoline, isoquinoline, indole, 3,4-methylenedioxyphenyl, piperazine, piperidine, morpholine and pyrrolidine .

When R is a mono or polysubstituted phenyl, Calkyl, in particular ethyl, C1-3 polyhalogenoalkyl, in particular, trifluoromethyl, and halogen, in particular chlorine, are preferred as substituents.

A preferred group of compounds of formula (I) is that in which n is 0, Y is NH, R1 and R2 are hydrogen, R is a substituted phenyl and the dashed line indicates a bond.

The following compounds are particularly preferred:

- N- (3-chloro-4-ethylphenyl) -N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea - N- (4-chlorophenyl) -N' - (5 -oxo-2,5-dihydro-1H-pyrrol-3-yl) urea.

Another group of preferred compounds of formula (I) is that in which n is 0, Y is oxygen, X is -NH-CO-NH-, R is phenyl bearing one or more substituents selected from C1-4alkyl and halogen, are defined as above and the dotted line a link.

Particularly preferred are the following compounds:

3-dimethylaminomethyl-4- [N- (4-ethyl-3-chlorophenyl) aminocarbonylamino] -2 (5H) -furanone

3-dimethylaminomethyl-4- (N- (4-chlorophenyl) aminocarbonylamino] -2 (5H) -furanone

The present invention also relates to pharmaceutical formulations containing a pharmaceutically effective amount of one or more compounds of formula (I) in admixture with pharmaceutically acceptable excipients.

Another purpose of the invention is to make available processes for the preparation of the compounds of formula (I).

Compounds of formula (I) in which the dashed line indicates a bond and which bear an -NH- group in position 4 can be prepared by reacting a compound of formula (II)

wherein n, Y, R1 and R2 are defined as for the compounds of formula (I), with a compound of formula (III)

W-NH2 (III)

where W is chosen from

they are defined as for the compounds of formula (I).

The reaction is generally carried out in solution, operating in a solvent such as an alcohol (methanol, ethanol, propanol or butanol) or an aromatic hydrocarbon (benzene, toluene, xylene) at reflux or at 50-150 ° C, preferably 80 -120 ° C. The reaction can also be carried out without a solvent or with a small amount of a high boiling solvent, such as e.g. toluene, xylene, dioxane, dimethylformamide, nitromethane or n-butanol, if necessary to obtain a clear melt. A small amount of a Lewis acid, such as p-toluenesulfonic acid, may be used if necessary.

Compounds of formula (I) in which the dashed line indicates a bond and X

are preferably obtained for

reaction of a compound of formula (II)

where n, Y are defined as for the compounds of formula (I), with a compound of formula (ΙII)

wherein R being defined as for the compounds of formula (I).

The reaction is generally carried out in an inert solvent, such as tetrahydrofuran, dimethoxyethane, dioxane, toluene, xylene, at a temperature between 0 ° C and the reflux temperature of the solvent, preferably 20-50 ° C.

The compounds of formula (ΙI) in which n = 0 are known products, the preparation of which is described for example in Bull. Chem. Soc. Jap. Vol. 60, p. 21392150, (1987) and EP 971115391.1. The compounds of formula (ΙI) in which n = 1 can be obtained from the compounds of formula (II) by fusion with ammonium salts, such as for example. ammonium acetate.

The compounds of formula (III ') are known (J. Org. Chem., 28, 1805-1811, 1963; DE 817 602; J. Org. Chem. Vol. 29, page 2592, (1964); J. Org. Chem., Vol.

31, p. 2658, (1966) and Ang. Ch. Vol. 79, p. 726, (1967)) and some of them are commercially available.

The compounds of formula (II) in which n is 0 and Y is oxygen are known and can be prepared starting from the halogenacetacetates of formula (IV)

wherein Hai is halogen and R3 is C1-3 alkyl, by heating them in a solvent.

The compounds of formula (II) in which n is 0 and Y is NH can be prepared, for example, according to the method described in J. Chem. Soc., Perkin I, 1973, 2907-2910

The compounds of formula (II) in which n is 0 and Y is sulfur are known compounds described for example in Bull. Chem. Soc. Jpn., 52 (12), 3601-3605, (1979) and in Il Farmaco, 47 (12), 1495-1511, 1992.

The compounds of formula (II) in which n is 1 and Y is oxygen are known compounds, which can be prepared for example according to the process illustrated in Tetrahedron Letters Vol. 32, No. 26, p. 3063-3066, 1991.

The compounds of formula (II) in which n is 1 and Y is NH are known and can be prepared, for example, according to the processes illustrated in EP-A-0 278 742 and in J. Antibiot. (1980), 33 (2), 173-81.

The compounds of formula (I) in which X is -CO-NH- or -CO-NH-NH- and the dotted line indicates a bond are prepared by reacting a carboxylic acid of formula (V)

where n, Y, R1 and R2 are defined as for the compounds of formula (I), with a compound of formula (VI)

wherein Z is R or R-NH, R being as previously defined, upon condensation of the carboxyl group of the compound of formula (IV), for example by its transformation into acyl chloride, hydroxysuccinimido ester, pentafluophenyl ester or by means of dicyclohexylcarbodiimide.

Compounds of formula (I) in which X is -CO- and the dashed line indicates a bond are prepared by reacting a compound of formula (VII)

in which n, R1, R2 and Y are defined as for the compounds of formula (I), according to the following reaction scheme:

a) KCN / DMF or 3-benzyl-5- (2-hydroxyethyl) -4-methylthiazolium chloride / EtOH b) NBS / CC14

c) NaOH

The compounds of formula (I) where X is and the line

dashed indicates a bond are prepared by reacting a compound of formula (VIII)

wherein n, R1, R2 and Y are defined as for the compounds of formula (I), with a Wittig reagent then optionally separating the cis and trans isomers by crystallization or chromatography.

The compounds of formula (VII) in which Y = O are known (Beilstein, vol. 17, p.

249; Beilstein, you. 17 (3), p. 4300).

The compounds of formula (V) and (VIII) are known in the art (see eg Synthesis 155, 1996).

Alternatively, the above compounds of formula (I) in which X is -CH = CH- and the dotted line indicates a bond can be prepared by reaction of Wittig's reagents of formula (IX) (e.g. triphenylphosphoranilidenemethyl) -5H -furan-2-one is a compound known from J.Chem.Res. (8) 1985, p. 102) or the corresponding Homer-Hemmons reagents of formula (X) (J.Am.Chem.Soc.

1033, 1982), with R-CHO aldehydes, according to the following scheme.

The compounds of formula (I) in which X = -CO-CH = CH- can be obtained by reaction of Wittig's reagents of formula (XI) with R-CHO aldehydes, according to the following scheme.

The compounds of formula (I) in which X is a cyclopropan-1,2-di-yl residue can be obtained from corresponding compounds of formula (I) in which X = -CH = CH- by classical cyclopropanation reactions, for example with the Simmons-Smith reaction or dimethylsulfoxonium methylide.

The compounds of formula (I) in which the dashed line does not indicate any bond can be obtained starting from the corresponding unsaturated compounds of formula (I) by chemical or catalytic reduction.

The compounds of formula (I) in which -A in which p = 1 and A - OH o

can be prepared by reaction of compounds of formula (I) in which

R] is H with formaldehyde or, respectively, with formaldehyde and an amine of the formula under the conditions of the Mannich reaction.

The compounds of formula (I) in which R, is a group of formula in which p is different from 1 and A is different from are prepared by reaction of a dicarbonyl compound of formula (II) in which R1 is H with a compound of formula p where T is a leaving group, e.g. a halogen, followed by the reaction with a compound of formula W-NH2 (III), according to the following scheme.

The compounds according to the invention were pharmacologically tested against four human tumor cell lines: HT 29 (colon cancer), PC 3 (prostate cancer), H 460M (lung cancer), MCF-7 (breast cancer) . After 144 hours of cell incubation with the compound to be tested, cytotoxicity was determined using the MTT assay (Mosman, T. "Rapid Colorimetrie Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay"; J. Immunolog. Methods, (1983), 65, 66; Green, L.M., Rapid Colorimetrie Assay for Celi Viability; Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines ", J. Immunol. Methods, (1984), 70, 257-268).

From the data obtained it emerged that the compounds according to the present invention are endowed with a marked activity against solid tumors, in particular colon tumors.

The compounds according to the present invention can be administered in doses ranging from 0.01 mg to 0.4 g per kg of body weight per day. A preferred method of administration is that which uses a dosage of from about 1 mg to about 50 mg per kg of body weight per day, using unit doses such as to be administered in 24 hours from about 70 mg to about 3.5 g of the active substance. a patient with a weight of about 70 kg. Such a mode of administration can be adjusted to obtain a better therapeutic effect. For example, the doses can be adjusted in consideration of the patient's therapeutic situation. The active compounds according to the invention can be administered orally, intravenously, intramuscularly or subcutaneously.

The pharmaceutical compositions according to the present invention contain therapeutically effective amounts of at least one compound according to the invention mixed with excipients compatible with pharmaceutical use.

The oral compositions generally comprise an inert diluent or an edible carrier and can be enclosed in gelatin capsules or reduced into tablets. Other possible forms of oral administration are represented by capsules, pills, elixirs, suspensions or syrups.

Tablets, pills, capsules and similar compositions may contain the following ingredients (in addition to the active compound): a binder, such as microcrystalline cellulose, tragacanth or gelatin; a carrier such as starch or lactose, a disintegrant such as alginic acid, primogel, corn starch and the like; a lubricant such as magnesium stearate; a fluidifier such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin or a flavoring such as mint flavor, methyl salicylate or orange flavor. When the selected composition is in capsule form, it may additionally contain a liquid carrier such as a fatty oil. Other compositions may contain various materials, for example coating agents (for tablets and pills) such as sugar or shellac. The material used in the preparation of the compositions should be pharmaceutically pure and non-toxic at the dosages employed.

For the preparation of pharmaceutical compositions for parenteral administration the active ingredient can be included in solutions or suspensions, which may additionally contain the following components: a sterile diluent such as water for injections, saline, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates are agents for adjusting the tonicity of the solution, such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, single-dose syringes, glass or plastic ampoules.

The present invention will be further described with reference to the examples provided below for illustrative and non-limiting purposes.

Preparation 1: 4- (3-chloro-4-ethylphenyl) semicarbazide

A mixture of 3-chloro-4-ethylphenylurea (1.0 g), 98% hydrazine hydrate (0.73 ml) and water (0.36 ml) is refluxed for 0.5 h. Ethanol (3 ml) is added to the dense mixture obtained and the reflux heating is continued for a total of 16 hours. the solution obtained is carefully concentrated to dryness and the residue obtained is dissolved in ethanol (5 ml) and acidified with 37% -HCl. After 0.5 hours the precipitate formed is recovered by filtration and redissolved in water (15 ml), removing the insoluble portion by hot filtration, the aqueous solution is brought to pH 9 with 20% NaOH and extracted with ethyl acetate (2 x 50 me). The combined organic phases are dried and concentrated to dryness, yielding a residue which is purified by column chromatography (silica; eluent ethyl acetate) yielding the 4- (3-chloro-4-ethylphenyl) semicarbazide (277 mg) which is used without further purification.

Similarly they are prepared:

4- (4-chlorophenyl) semicarbazide, m.p. 263-265 ° C;

4- (3-chloro-4-methylphenyl) semicarbazide;

4- (3-chloro-4-propylphenyl) semicarbazide;

4- (3-chloro-4 - ((2-methyl) propyl) phenyl) semicarbazide;

4- (3-chloro-4-butylphenyl) semicarbazide;

4- (4-bromophenyl) semicarbazide;

4- (4-methylphenyl) semicarbazide;

4- (3-trifluoromethylphenes) semicarbazide;

4- (3-bromophenyl) semicarbazide;

4- (4-trifluoromethylphenyl) semicarbazide;

4- (4-methoxyphenyl) semicarbazide;

4- (3,4-dicIorophenyl) semicarbazide;

4- (3-chloro-4-trifluoromethylphenyl) semicarbazide;

4- (3,5-bis (trifluoromethyl) phenyl) semicarbazide.

Preparation 2: 4-chlorophenylacetamide

A suspension of 4-clophenylacetic acid (1.7g) in thionyl chloride (5ml) is stirred at room temperature for 3 hours. The excess of thionyl chloride is evaporated by distillation under vacuum, keeping the temperature below 30 ° C. The residue is taken up with toluene and the solvent removed by distillation under vacuum. This operation is repeated three times. Finally, the residue is dissolved in THF (50 mL) and ammonia is bubbled into the solution, keeping the temperature at about 10 ° C. The suspension obtained is diluted with water to give a clear solution which is concentrated to a small volume. The precipitate is recovered by filtration and washed on the filter with water / THF 7/3, to give 4-chlorophenylacetamide (1.4 g).

m.p. 173-175

Similarly, the following products are prepared:

4-bromophenylacetamide;

4-methylphenylacetamide;

3- (trifluoromethyl) phenylacetamide;

3-bromophenylacetamide;

4- (trifluoromethyl) phenylacetamide;

4-methoxyphenylacetamide;

3.4-dichlorophenylacetamide;

3.5-bis (trifluoromethyl) phenylacetamide;

1 -naphthylacetamide;

2-naphthylacetamide;

2-bromophenylacetamide;

2-fluorophenylacetamide;

2-chlorophenylacetamide;

2.4-dichlorophenylacetamide;

2-methoxyphenylacetamide;

2 - (tri flu or ometi 1) hay 1 acetammi;

2-methylphenylacetamide;

Preparation 3

The following aroyl isocyanates are prepared according to the procedure described by A. J. Speziale et al. (J. Org. Chem., 28, 1805-1811, 1963) by reaction of the appropriate benzamides with oxalyl chloride:

3.4-dichlorobenzoylisocyanate

4-chlorobenzoylisocyanate

4-bromobenzoylisocyanate

4-trifluoromethylbenzoylisocyanate

4-chloro-3-methylbenzoylisocyanate

Example 1:

A mixture of 3-chloro-4-ethylphenylurea (198 mg) and tetramic acid (G. Lowes et al, J. C. S. Perkin I, 2907-2910, 1973) (100 mg) in absolute ethanol / toluene 2/1 (6 ml) it is heated under reflux, removing Γ ethanol by distillation. When all Γ ethanol has been removed, further absolute ethanol (2 ml) is added to the reaction mixture and its removal from the reaction mixture is repeated by distillation.

The addition of absolute ethanol (2 ml) and its removal by distillation is subsequently repeated, the reaction mixture is evaporated to dryness and the residue obtained is purified by column chromatography (silica; eluent to give the N- (3- chloro-4-ethylphenyl) -N '- (5-oxo-2, 5-dihydro- 1 H-pyrrol-3-yl) urea (49 mg).

m.p. 233-235 ° C

1H-NMR (DMSO-d6): 1.15 ppm (t, 3H), 2.65 ppm (q, 2H), 4.10 ppm (s, 2H), 5.55 (s, IH), 7.23 ppm (s, 2H), 7.40 ppm (br s, 1H), 7.65 ppm (s, 1H), 9.0 ppm 8s, 1H), 9.33 ppm (s, 1H).

Similarly, the following products are prepared, using as starting products the suitable commercially available ureas, known or prepared with known methods:

N-phenyl-N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea, m.p. 225-227 ° C

N- (4-chlorophenyl) -N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea

N- (4-fluorophenyl) - N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea;

N- (4-chloro-3-ethylphenyl) - N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea;

N- (3-chloro-4-methylphenyl) - N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea;

N- (3-chloro-4-propylphenyl) - N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea;

N- (3-chloro-4 - ((2-methyl) propyl) phenyl) - N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea;

N- (3-chloro-4-butylphenyl) - N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea;

N- (4-tert-butyl-3-fluorophenyl) - N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea; N- (4-hydroxyphenyl) - N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea;

N- (3-methoxyphenyl) - N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea;

Example 2:

A stirred suspension of 5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one (384 mg), 4-chlorophenylurea (512 mg) and traces of p-toluenesulfonic acid monohydrate in toluene (9 ml ) is heated under reflux for one hour, azeotropically removing the water formed by Dean-Stark.

After cooling to room temperature, the precipitate present is separated by filtration and carefully washed on the filter with toluene, to give a solid (420 mg) which is suspended in ethanol (10 ml) upon boiling. After cooling at rt the solid is recovered by filtration, to give N- (4-chlorophenyl) -N '- (2-methyl-6-oxo-3,6-dihydro-2H-piran-4-yl) urea (385 mg), m.p. 236-238 ° C

Similarly, the following products are obtained by reaction of 5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one or 5,6-dihydro-4-hydroxy-2H-pyran-2- one (J. d'Angelo et al, Tetrahedron Letters, 32 (26), 3063-3066, 1991) with the appropriate ureas:

N-phenyl-N <,> - (2-methyl-6-oxo-3,6-dihydro-2H-piran-4-yl) urea, m.p. 232-233 ° C; N- (3-chloro-4-ethylphenyl) -N '- (2-methyl-6-oxo-3,6-dihydro-2H-piran-4-yl) urea, m.p. 240-241 ° C;

N- (4-chlorophenyl) -N '- (6-oxo-3,6-dihydro-2H-pyran-4-yl) urea;

N-phenyl-N '- (6-oxo-3,6-dihydro-2H-piran-4-yl) urea;

Example 3:

A stirred mixture of tetronic acid (tetrahydrofuran-2,4-dione; 200 mg), 4-chlorobenzamide (312 mg) and traces of p-toluenesulfonic acid monohydrate (5 mg) in toluene (3 ml) is refluxed for 4 hours, azeotropically removing the water formed by Dean-Stark.

After cooling to room temperature the solid obtained is recrystallized from methanol. After drying under vacuum at 50 ° C 82 mg of N- (5-oxo-2,5-dihydrofuran-3-yl) -4-chlorobenzamide are obtained.

m.p. 260 ° C

Similarly, the following products are prepared starting from the appropriate benzamides:

N- (5-oxo-2,5-dihydrofuran-3-yl) benzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-chloro-4-methylbenzamide, m.p. 228-230 ° C;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-chloro-4-ethylbenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-chloro-4-propylbenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-chloro-4 - ((2-methyl) propyl) benzamide; N- (5-oxo-2,5-dihydrofuran-3-yl) -3-chloro-4-butylbenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -4-trifluoromethylbenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -2-bromobenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-bromobenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -4-bromobenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -4-methylbenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-trifluoromethylbenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -4-methoxybenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3,4-dichlorobenzamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-chloro-4-trifluoromethylbenzamide; N- (5-oxo-2,5-dihydrofuran-3-yl) -3,5-bis (trifluoromethyl) benzamide; Example 4:

A stirred mixture of tetronic acid (tetrahydrofuran-2,4-dione; 80 mg), 4-chlorobenzenesulfonamide (162 mg) and p-toluenesulfonic acid monohydrate (2 mg) in toluene (1 ml) is refluxed for 2 hours, by azeotropically removing the water formed by Dean-Stark. After cooling to room temperature, the precipitate is recovered by filtration, washed on the filter with ethanol and recrystallized from ethanol. After cooling at rt N- (5-oxo-2,5-dihydrofuran-3-yl) -4-chlorobenzenesulfonamide (90 mg) is obtained, m.p. 265-268 ° C

Similarly, the following products are prepared starting from the appropriate benzenesulfonamides:

N- (5-oxo-2,5-dihydrofuran-3-yl) benzenesulfonamide

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-chloro-4-methylbenzenesulfonamide N- (5-oxo-2,5-dihydrofuran-3-yl) -4-trifluoromethylbenzamide

N- (5-oxo-2,5-dihydrofuran-3-yl) -2-bromobenzenesulfonamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-bromobenzenesulfonamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -4-bromobenzenesulfonamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -4-methylbenzenesulfonamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-trifluoromethylbenzenesulfonamide; N- (5-oxo-2,5-dihydrofuran-3-yl) -4-methoxybenzenesulfonamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3,4-dichlorobenzenesulfonamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-chloro-4-trifluoromethylbenzenesulfonamide;

Example 5;

A mixture of 3-chloro-4-ethylaniline (200 mg), tetronic acid (tetrahydrofuran-2,4-dione; 128 mg) and traces of p-toluenesulfonic acid monohydrate (1 mg) in toluene (3 ml) is heated to reflux for 1.5 hours, azeotropically removing the water formed by Dean-Stark. The mixture is cooled to 40 ° C and the solid present is recovered by filtration, washed on the filter with toluene and finally re-crystallized from methanol, to give 4- (3-chloro-4-ethylphenylamino) -5H-furan-2-one ( 102 mg).

m.p. 159-160 ° C

In a similar way, the following products are prepared by reaction of tetronic acid with the appropriate anilines:

4- (4-chlorophenylamino) -5H-furan-2-one, m.p. 220-222 ° C;

4-phenylamino-5H-furan-2-one, m.p. 218-220 ° C;

4- (3-chloro-4-methylphenylamino) -5H-furan-2-one;

4- (3-chloro-4-propylphenylamino) -5H-furan-2-one;

4- (3-chloro-4 - ((2-methyl) propylphenylamino) -5H-furan-2-one;

4- (3-chloro-4-butylphenylamino) -5H-furan-2-one;

4- (4-bromophenylamino) -5H-furan-2-one;

4- (4-methylphenylamino) -5H-furan-2-one;

4- (3-trifluoromethylphenylamino) -5H-furan-2-one;

4- (3-bromophenylamino) -5H-furan-2-one;

4- (4-trifluoromethylphenylamino) -5H-furan-2-one;

4- (4-methoxyphenylamino) -5H-furan-2-one;

4- (3,4-dichlorophenylamino) -5H-furan-2-one;

4- (3-chloro-4-trifluoromethylphenylamino) -5H-furan-2-one;

4- (3,5-bis (trifluoromethyl) phenylamino) -5H-furan-2-one;

Example 6:

A suspension of tetramic acid (99 mg) and 3-chloro-4-ethylaniline (186 mg) in toluene (2 ml) is heated to reflux for 1 hour in a nitrogen atmosphere, azeotropically removing the water formed by Dean-Stark. The suspension is cooled to 60 ° and filtered at this temperature. The solid is washed on the filter with absolute ethanol and recrystallized from absolute ethanol to give 4- (3-chloro-4-ethylphenylamino) -1,5-dihydropyrrol-2-one (260 mg).

m.p. 240-242 ° C

In a similar way, the following products are prepared by reaction of tetramic acid with the appropriate anilines:

Example 7:

A mixture of 4-hydroxy-5H-thiophen-2-one (thiotetronic acid; 232 mg), 3-chloro-4-ethylaniline (3 1 1 mg) and trace amounts of p-toluenesulfonic acid monohydrate (2 mg) in toluene ( 2 ml) is heated under reflux for 30 minutes, azeotropically removing the water formed by Dean-Stark. After cooling to room temperature, the solid present is recovered by filtration and washed with ethyl acetate, to give 4- (3-chloro-4-ethylphenylamino) -5H-thiophen-2-one (300 mg),

m.p. 186-187 ° C

In a similar way, the following products are prepared by reaction of 4-hydroxy-5H-thiophen-2-one (thiotetronic acid) with the appropriate anilines:

4- (4-chlorophenylamino) -5H-thiophen-2-one;

4-phenylamino-5H-thiophen-2-one;

4- (3-chloro-4-methylphenylamino) -5H-thiophen-2-one;

4- (3-chloro-4-propylphenylamino) -5H-thiophen-2-one;

4- (3-chloro-4 - ((2-methyl) propylphenylamino) -5H-thiophen-2-one;

4- (3-chloro-4-butylphenylamino) -5H-thiophen-2-one;

4- (4-bromophenylamino) -5H-thiophen-2-one;

4- (4-methylphenylamino) -5H-thiophen-2-one;

4- (3-trifluoromethylphenylamino) -5H-thiophen-2-one;

4- (3-bromophenylamino) -5H-thiophen-2-one;

4- (4-trifluoromethylphenylamino) -5H-thiophen-2-one;

4- (4-methoxyphenylamino) -5H-thiophen-2-one;

4- (3,4-dichlorophenylamino) -5H-thiophen-2-one;

4- (3-chloro-4-trifluoromethylphenylamino) -5H-thiophen-2-one;

4- (3,5-bis (trifluoromethyl) phenylamino) -5H-thiophen-2-one;

Example 8:

In a nitrogen atmosphere, a mixture of N- (4-chlorobenzoyl) hydrazine (341 mg), tetonic acid (tetrahydrofuran-2,4-dione; 200 mg) and traces of ptoluenesulfonic acid (1 mg) in toluene (3 ml) it is heated under stirring under reflux for 2 hours. After cooling to 40 ° C, the solid present is separated by filtration and recrystallized from methanol. After drying under vacuum at 40 ° C, 360 mg of N '- (5-oxo-2,5-dihydrofuran-3-yl) -4-chlorobenzoylhydrazide are obtained.

m.p. 228-232 ° C.

Example 9:

A suspension of 3-chloro-4-methylbenzoic acid (0.5 g) in donyl chloride (3 ml) is heated at 50 ° C for two hours. The solution obtained is concentrated to dryness and the residue is taken up with n-heptane and reconcentrated to dryness. This operation is repeated twice. The oily residue obtained is redissolved in tetrahydrofuran and dropped in a solution of 4-hydrazino-5H-furan-2-one (Arch. Farm. 320. 749-755, (1987); 360 mg) in anhydrous THF (50 ml) containing triethylamine (0.6 ml), cooling to 0 ° C. The red suspension obtained is left under stirring at room temperature for 2 h and is subsequently poured into a 20% NaH2P03 solution (100 ml). After extraction with ethyl acetate (3x100 ml) the combined organic phases are dried over Na2SO4 and evaporated to dryness. The obtained residue is crystallized from ethyl acetate, to give

N '- (5-oxo-2,5-dihydrofuran-3-yl) -3-chloro-4-methylbenzoylhydrazide (312 mg). m.p. 21 1-213 ° C.

Example 9a

Using the procedures described in examples 8 and 9 the following products are prepared:

N '- (5-oxo-2,5-dihydrofuran-3-yl) -3,5-bis (trifluoromethyl) benzoylhydrazide; Example 10;

A solution of 4-chlorobenzenesulfonyl chloride (710 mg) in methylene chloride (5 ml) is dropped into a suspension of 4-hydrazino-5H-furan-2-one (Arch. Farm. 320, 749-755, (1987); 300 mg) in methylene chloride (30 ml) containing pyridine (0.52 ml), cooling to 0- ° C. At the end of the dripping, the reaction mixture is brought to room temperature and after 1.5 hours it is concentrated to dryness. The residue obtained is taken up with water and left under stirring for 1 hour at room temperature. The solid recovered after filtration is resuspended under heat in ethyl acetate (6 ml), filtered and finally purified by column chromatography (methylene chloride / methanol 9/1). The fractions containing the product are combined, concentrated to dryness and the residue leached in ethyl ether, to give N '- (5-oxo-2,5-dihydrofuran-3-yl) -4-chlorobenzenesulphonylhydrazide (418 mg).

m.p. 224-226 ° C

Similarly, the following products are prepared by reaction of 4-hydrazino-5H-furan-2-one with suitable sulfonyl chlorides:

N '- (5-oxo-2,5-dihydrofuran-3-yl) benzenesulfonylhydrazide, m.p. 208-209 ° C

Example 1 1:

A solution of tetronic acid (220 mg) in water (15 ml) is added dropwise to a solution of 3-chloro-4-methylphenylhydrazine (350 mg) in ethanol (20 ml), heated to 50 ° C. At the end of the addition, the reaction mixture is heated under reflux for two hours and subsequently concentrated to dryness. The residue obtained is purified by column chromatography (silica; eluent CHCl3 / MeOH 9/1) and subsequently crystallized from tert-butyl methyl ether, to give N- (3-chloro-4-methylphenyl) -N '- (5- oxo-2,5-dihydrofuran-3-yl) hydrazine (209 mg).

m.p. 128-130 ° C.

Similarly, the following products are prepared by reaction of tetronic acid with the appropriate hydrazines:

Example 12:

A stirred suspension of 4- (4-chlorophenyl) semicarbazide (250 mg), tetronic acid (134 mg) and traces of p-toluenesulfonic acid monohydrate (5 mg) in anhydrous toluene (10 ml) is refluxed for 2 hours, by azeotropically removing the water formed by Dean-Stark. After this period the reaction mixture is topped up with methanol (10 ml) and the reflux heating is continued for another 0.5 hours. after cooling to room temperature the precipitate formed is recovered by filtration, to give 1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (4-chlorophenyl) semicarbazide (162 mg),

m.p. 229-23 1 ° C

Similarly they are prepared:

1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3-chloro-4-ethylphenyl) semicarbazide, m.p.

210-213 ° C

1- (5-oxo-2,5-dihydrofuran-3-yl) -4-phenylsemicarbazide, m.p. 218-222 ° C 1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3-chloro-4-methylphenyl) semicarbazide; 1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3-chloro-4-propylphenyl) semicarbazide; 1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3-chloro-4 - ((2-methyI) propyl) phenyl) semicarbazide;

1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3-chloro-4-butylphenyl) semicarbazide; 1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (4-bromophenyl) semicarbazide;

1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (4-methylphenyl) semicarbazide;

1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3-trifluorometiIphenyl) semicarbazide; 1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3-bromophenyl) semicarbazide;

1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (4-trifluoromethylphenyl) semicarbazide; 1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (4-methoxyphenyl) semicarbazide;

1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3,4-dichlorophenyl) semicarbazide;

1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3-chloro-4-trifluoromethylphenyl) semicarbazide;

1- (5-oxo-2,5-dihydrofuran-3-yl) -4- (3,5-bis (trifluoromethyl) phenyl) semicarbazide.

Example 13:

. A stirred suspension of 1-phenylsemicarbazide (1.0 g), tetronic acid (0.66 g) and traces of p-toluenesulfonic acid monohydrate (5 mg) in anhydrous toluene (10 ml) is refluxed for one hour, azeotropically removing the water formed by Dean-Stark. After cooling to room temperature, the toluene is removed by decantation and the solid residue is taken up under stirring with boiling methanol (20 ml) for two hours. The solid is recovered by filtration (1.02 g) and redissolved in methanol (60 ml) at boiling, removing the hot undissolved portion by filtration. By concentration of the methanolic solution at about 30 ml the crystallization of 4- (5-oxo-2,5-dihydrofuran-3-yl) - 1-phenylsemicarbazide (0.76 g) is obtained.

m.p. 221-223 ° C

Example 14:

A stirred mixture of 4-chlorophenylacetamide (170 mg), tetronic acid (100 mg) and traces of p-toluenesulfonic acid (1 mg) in anhydrous toluene (2ml) is refluxed for one hour in a nitrogen atmosphere, azeotropically removing the water formed by Dean-Stark. After 4 hours the reaction mixture is cooled to room temperature and purified by column chromatography (silica; eluent ethyl acetate). The fractions containing the product are concentrated to a small volume and the separated solid is recovered by filtration, to give N- (5-oxo-2,5-dihydrofuran-3-yl) -4-chlorophenylacetamide (30 mg).

m.p. 161-162 ° C

N- (5-oxo-2,5-dihydrofuran-3-yl) -4-bromophenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -4-methylphenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3- (trifluoromethyl) phenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3-bromophenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -4- (trifluoromethyl) phenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -4-methoxyphenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3,4-dichlorophenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -3,5-bis (trifluoromethyl) phenylacetamide; N- (5-oxo-2,5-dihydrofuran-3-yl) -1-naphthylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -2-naphthylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -2-bromophenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-II) -2-fluorophenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -2-chlorophenylacetarmnide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -2,4-dichlorophenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -2-methoxyphenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -2- (trifluoromethyl) phenylacetamide;

N- (5-oxo-2,5-dihydrofuran-3-yl) -2-methylphenylacetamide;

Example 15:

A stirred suspension of DL-4-chlorophenylalanine ethyl ester (1.27 g; obtained by neutralization of the corresponding hydrochloride with a saturated solution of sodium bicarbonate and subsequent extraction with ethyl acetate), tetronic acid (0.55 g) and traces of p- acid toluenesulfonic (5 mg) in toluene (30 ml) is heated under reflux for two hours, azeotropically removing the water formed by Dean-Stark. After cooling to room temperature, the reaction mixture is partitioned between water (100 ml) and ethyl acetate (2 x 50 ml). The combined organic phases are dried and evaporated to dryness to give a residue which is purified by column chromatography (silica, eluent ethyl acetate) and subsequent leaching in ethyl ether. Ethyl DL-2- (5-Oxo-2,5-dihydrofuran-3-ylamino) -4-chlorophenylpropionate (544 mg) is thus obtained.

m.p. 127-129 ° C.

Similarly, they are prepared:

DL-2- (5-Oxo-2,5-dihydrofuran-3-ylamino) ethyl phenylpropionate

A solution of ethyl DL-2- (5-oxo-2,5-dihydrofuran-3-ylamino) -4-chlorophenylpropionate (395 mg) in methanol (10 ml) containing IN NaOH (1.9 ml) is left at room temperature for 18 hours. the solution is subsequently concentrated to a small volume and acidified to pH 2 with hydrochloric acid. The separated precipitate is left under stirring for 12 hours, subsequently recovered by filtration and washed on the filter with water. After drying at 50 ° C under vacuum for one night, DL-2- (5-oxo-2,5-dihydrofuran-3-ylamino) -4-chlorophenylpropionic acid (307 mg) is obtained, m.p. 218-220 ° C.

Similarly, they are prepared:

DL-2- (5-Oxo-2,5-dihydrofuran-3-ylamino) phenylpropionic acid; DL-2- (5-Oxo-2,5-dihydrofuran-3-ylamino) -4-hydroxyphenylpropion acid

co;

DL-2- (5-Oxo-2,5-dihydrofuran-3-ylamino) -4-bromophenylpropionic acid;

DL-2- (5-Oxo-2,5-dihydrofuran-3-ylamino) -4-fluorophenylpropionic acid:

DL-2- (5-Oxo-2,5-dihydrofuran-3-ylamino) -4-nitrophenylpropionic acid.

Example 17:

Sodium hydride (60% suspension in mineral oil) is added to a suspension of 4-amino-5H furan-2-one (obtained by fusion of tetronic acid with ammonium acetate; 500 mg) in anhydrous THF (25 ml); 110 mg) and the resulting suspension is heated at 40 ° C for two hours. After cooling to room temperature, benzoylisocyanate (735 mg) is added and stirred at room temperature for 18 hours. the reaction mixture is added with methanol and evaporated to dryness. The residue is taken up with a small volume of a mixture of ethyl acetate and water slightly acidified with NaH2P04. The insoluble solid in the two phases is recovered by filtration, washed on the filter with water and a little ethyl acetate, and subsequently recrystallized from methanol, to give 1-benzoyl-3- (5-oxo-2,5-dihydrofuran-3 -yl) urea (120 mg).

Similarly, the following products are prepared:

1- (3,4-dichlorobenzoyl) -3- (5-oxo-2,5-dihydrofuran-3-yl) urea;

A solution of 4-methylsulfonyl isocyanate ( 197 mg) in 1,2-dimethoxyethane (2 ml), cooling to 5 ° C. the suspension is stirred at 5 ° C for one hour, and then at room temperature for 24 hours.

The precipitate present is recovered by filtration to give 1- (4-methylsulfonyl) -3- (5-oxo-2,5-dihydrofuran-3-yl) urea.

m.p. 226 ° C with decomposition.

Similarly, they are prepared:

1- (4-chlorosulfonyl) -3- (5-oxo-2,5-dihydrofuran-3-yl) urea (m.p. 235 ° C with decomposition);

1-phenylsulfonyl-3- (5-oxo-2,5-dihydrofuran-3-yl) urea.

Example 19:

A suspension of N- (4-chlorophenyl) -N '- (5-oxo-2,5-dihydrofuran-3-yl) urea (EP971 15391.1 dated 5/9/1997; 505 mg), dimethylamine (0.43 ml of a 33% solution in ethanol) and 37% aqueous formaldehyde (0.18 ml) in glacial acetic acid (5 ml) is heated under reflux for two hours. the solution obtained is cooled to room temperature and poured into 2N NaOH (44 ml) and subsequently extracted with ethyl acetate (2x50 ml). The combined organic phases are washed with brine (50 ml), dried and concentrated to a small volume. The precipitate obtained is recovered by filtration and dried under vacuum at 50 ° C for one hour, to give N- (4-chlorophenyl) -N '- (5-oxo-4-dimethylaminomethyl-2,5-dihydrofuran-3 -yl) urea (245 mg).

m.p. 183-186 ° C

This product (0.15 g) is suspended in absolute ethanol (1 ml) and a 1 N solution of HCl in ethyl ether (3.8 ml) is added. The suspension is left under stirring at room temperature for two hours. The precipitate is recovered by filtration to give N- (4-chlorophenyl) -N '- (5-oxo-4-dimethylaminomethyl-2,5-dihydrofuran-3-yl) urea hydrochloride (156 mg).

m.p. 250-253.

Similarly, the following compounds are prepared by reaction of

A solution of 4- (triphenylphosphoranylidenemethyl) -5H-furan-2-one (S. A. Gadir et al., J. Chem. Res., (8), 102-103, (1986); 358 mg) and 3.4, 5-trimethoxybenzaldehyde (240 mg) in anhydrous methylene chloride (6 ml) is heated under gentle reflux for three hours in a nitrogen atmosphere. The reaction mixture is concentrated to dryness and the residue obtained is leached with tert-butyl methyl ether (10 ml) under stirring for two hours. The solid is recovered by filtration and purified by column chromatography (silica; eluent: hexane / ethyl acetate 1/1). The mother liquors of the leaching with tert-butyl methyl ether, after dry concentration, are likewise purified by column chromatography, using the same previous conditions. The fractions containing the product from the two chromatographic purifications are combined and concentrated to dryness, giving a waxy solid (175 mg) which is leached under stirring for two hours in isopropyl ether. The solid is recovered by filtration to give 4- (3,4,5-trimethoxystyryl) -5H-furan-2-one (103 mg) as a mixture of E and Z isomers.

m.p. 106-108 ° C.

Similarly, the following products are prepared as mixtures of E and Z isomers

4- (3,4-diimethoxystyryl) -5H-furan-2-one;

4- (4-methoxystyryl) -5H-furan-2-one;

4-styryl-5H-furan-2-one;

Example 21:

A solution of 4- (triphenylphosphoranylidenemethyl) -5H-furan-2-one (S. A. Gadir et al., J. Chem. Res., (8), 102-103, (1986); 1.12 g) and 4-chlorobenzaldehyde ( 538 mg) in anhydrous methylene chloride (16 ml) is heated under gentle reflux for three hours in a nitrogen atmosphere. The reaction mixture is concentrated to dryness and the residue obtained is purified by column chromatography (silica; eluent: hexane / ethyl acetate 2/1). The fractions containing the product are combined and concentrated to dryness, to give 4- (4-chlorostyryl) -5H-furan-2-one as a mixture of isomers E and Z (370 mg). By treating this mixture with ethyl acetate, 4- (4-chlorostyryl) -5H-furan-2-one is recovered by filtration as pure E isomer (190 mg),

m.p. 198-200 ° C.

Similarly, the following products are prepared as pure geometric isomers:

E- 4- (4-br homostyryl) - 5H - furan-2 - one;

Z-4- (4-bromostyryl) -5H-furan-2-one;

E-4- (4-trifluoromethylstyril) -5H-furan-2-one;

Z-4- (4-trifluoromethylstyril) -5H-furan-2-one;

E-4- (3,4-dichlorostyryl) -5H-furan-2-one

Z-4- (3,4-dichlorostyryl) -5H-furan-2-one

E-4- (3-chloro-4-trifluoromethylstyril) -5H-furan-2-one;

Z-4- (3-chloro-4-trifluoromethylstyril) -5H-furan-2-one;

E- (3,5-bis (trifluoromethyl) styryl) -5H-furan-2-one.

Z- (3,5-bis (trifluoromethyl) styryl) -5H-furan-2-one.

Claims (18)

CLAIMS 1. Compounds of general formula (I) X R. (THE) C. m which: - Y is oxygen, sulfur or NH; - n is 0 or 1 - X is chosen from the group consisting of - Rj is selected from the group consisting of hydrogen, - (CH2) p-A, where they are hydrogen, C1-10alklyl, or Ra and Rb together with the nitrogen atom to which they are bound form a heterocyclic ring to 4-7 members; Re is hydrogen, alkyl or alkali or alkaline earth metal; - R is C3-7 cycloalkyl, C7-14arylalkyl, naphthyl, phenyl possibly mono or polysubstituted, aromatic heterocyclic ring or not 5- or 6-membered aromatic, optionally benzocondensed; - R2 is hydrogen or - the dotted line indicates an optional link; their pure or mixed stereoisomers and their salts with pharmaceutically acceptable acids or bases, with the conditions that: - when and the dotted line indicates a bond, R is different from phenyl or mono or polysubstituted phenyl; - when n = o C1-6alkyl and the dotted line indicates a bond, R is different from -NH-CO-NH-; - when p = 0, A is different from - when it is different from a 5-membered aromatic heterocyclic ring containing one nitrogen atom and one sulfur atom, for use as medicaments. 2. Compounds according to claim 1 for use as anticancer agents. 3. Compounds of general formula (I) in which: - Y is oxygen, sulfur or NH; - n is 0 or 1 - X is selected from the group consisting of - NH-CO-NH-, -NH-CO-, -NH-S02-, - R1 is selected from the group consisting of hydrogen, C1-10alkyl, - (CH2) p-A, where - they are hydrogen, and Rb together with the nitrogen atom to which they are bound form a heterocyclic ring with 4-7 members; Rc is hydrogen, alkyl or alkali or alkaline earth metal; - R is C3-7 cycloalkyl, C7-14arylalkyl, naphthyl, phenyl optionally mono or polysubstituted, 5 or 6 membered aromatic or non-aromatic heterocyclic ring optionally benzocondensed; - R2 is hydrogen or - the dashed line indicates an optional link; their pure or mixed stereoisomers and their salts with pharmaceutically acceptable acids or bases, with the conditions that: - when and the dashed line indicates a bond, R is different from phenyl or mono or polysubstituted phenyl; - when and the dashed line indicates a bond, R is different from phenyl and monosubstituted phenyl; - when and the dashed line indicates a bond, R is different from methyl, phenyl or benzyl; - when and the dashed line indicates a bond, R is different from 2,3,6-trimethylphenyl; - when and the dashed line indicates a bond, R is different from methyl; - when and the dashed line indicates a bond, R is different from phenyl and p-nitrophenyl; - when n = o C1-6alkyl and the dashed line indicates a bond, R is different from -NH-CO-NH-; - when - when it is different from a 5-membered aromatic heterocyclic ring containing a nitrogen atom and a sulfur atom. 4. Compounds according to claim 3, wherein R is a heterocyclic ring selected from the group consisting of pyridine, pyrrole, thiazole, thiophene, furan, imidazole, pyrazine, pyrimidine, quinoline, isoquinoline, indole, 3,4-methylenedioxyphenyl, piperazine, piperidine, morpholine and pyrrolidine. 5. Compounds according to claim 3, wherein R is a phenyl substituted with one or more groups selected from C1-4alkyl, C1-3 polyhalogenoalkyl and halogen. 6. Compounds according to claim 5, wherein R is a phenyl substituted with one or more groups selected from ethyl, tri fluoromethyl and chlorine. Compounds according to claim 3, wherein n is 0, Y is NH, X is -NH-CO-NH-, R1 and R2 are hydrogen, R is a substituted phenyl and the dashed line indicates a bond. 8. Compounds according to claim 7, having the following structures: - N- (3-chloro-4-ethylphenyl) -N '- (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea - N- (4-chlorophenyl) -N <,> - (5-oxo-2,5-dihydro-1H-pyrrol-3-yl) urea. 9. Compounds according to claim 3, wherein n is 0, Y is oxygen, X is NH-CO-NH-, R is phenyl having one or more substituents selected from and halogen, R, is -CH2-NRaRb, where Ra and Rb are defined as in claim 1 and the dashed line indicates a bond. 10. Compounds according to claim 9, having the following structures: 3-dimethylaminomethyl-4- [N- (4-ethyl-3-chlorophenyl) aminocarbonylamino] -2 (5H) -furanone. 3-dimethylaminomethyl-4- [N- (4-chlorophenyl) aminocarbonylamino] -2 (5H) -furanone. 1 1. Process for the preparation of a compound of formula (I) according to claim 1, which comprises the reaction of a compound of a compound of formula (II) wherein Y, R1 and R2 are defined as for the compounds of formula (I), with a compound of formula (I II) W-NH2 (III) they are defined as for the compounds of formula (I). 12. Process according to claim 11 wherein said reaction is carried out in solution at the reflux temperature optionally in the presence of a Lewis acid. 13. Process according to claim 12 wherein said reaction is carried out at 80-120 ° C. 14. Process according to claim 11, wherein said reaction is carried out in the absence of solvent, optionally in the presence of a Lewis acid. 15. Process for the preparation of a compound of formula (I) according to claim 1, wherein X is -NH-CO-NH-CO- or -NH-CO-NH-SO2-, which comprises the reaction of a compound formula (ΙΓ) wherein n, Y, R1 and R2 are defined as in claim 1, with a compound of formula (IIP) where W 'is R-CO or R-SO2, R being defined as in claim 1. 16. Process according to claim 15, wherein said reaction is carried out in an inert solvent at a temperature between 0 ° C and the reflux temperature of the solvent, preferably between 20 and 50 ° C. 17. Pharmaceutical compositions comprising at least one compound according to any one of claims 1- 10 together with a pharmaceutically acceptable carrier. 18. Use of a compound of formula (I) in which: - Y is oxygen, sulfur or NH; - n is 0 or 1 - X is chosen from the group consisting of - Ri is chosen from the group, consisting of hydrogen, where - they are hydrogen, C1-10alkyl, or Ra and Rb together with the nitrogen atom to which they are linked form a heterocyclic ring with 4-7 members; Rc is hydrogen, alkyl or alkali or alkaline earth metal; - R is C1-10alkyl, C3-7cycloalkyl, C7-14arylalkyl, naphthyl, phenyl optionally mono or polysubstituted, 5 or 6 membered aromatic or non-aromatic heterocyclic ring optionally benzocondensed; - R2 is hydrogen or C1-6alkyl; - the dashed line indicates an optional link; their pure or mixed stereoisomers and their salts with pharmaceutically acceptable acids or bases, with the conditions that: - when n = e the dashed line indicates a bond, R is different from -NH-CO-NH-; - when p = 0, A is different from -OH and NRaRb, in the manufacture of a drug with antitumor activity.