EP1173420A2 - Heterocyclic compounds having antitumor activity - Google Patents

Abstract

Compounds of general formula (I) in which: Y is O, S or NH; n is 0 or 1; X is selected from the group consisting of -NH-CO-NH, -NH-CO-, NH-SO2-, -NH-, -CO-NH-, -CO-NH-NH-, -NH-NH-CO-, -NH-NH-SO2-, -NH-CO-CO-, -NH-CO-CH2-, -NH-NH-,-NH-NH-CO-NH-, -NH-CO-NH-NH-, -CO-, -NH-SO2-NH-, -CO-NH-CO-NH-, -NH-CO-NH-CO-, -NH-CO-NH-SO2-, -NH-C(=NH)-NH-NH-, -NH-NH-C(=NH)-NH-, -CH=CH-, -CO-CH=CH-, -CH=CH-CO-, cyclopropan-1,2-di-yl, -NH-CH(COORC)-; R1 is selected from the group consisting of H, alkyl, -(CH2)p-A, wherein p = 0-4 and A = OH, -NRaRb, -COORc, -CONRaRb, -CONH(CH2)q-NRaRb, -CONH(CH2)q-COORc, wherein q = 1-4, Ra and Rb are H, alkyl, or Ra and Rb together with the nitrogen atom they are linked to form a 4-7 membered heterocyclic ring; Rc is H, alkyl or alkali or alkaline-earth metal; R is alkyl, cycloalkyl, arylalkyl, naphthyl, optionally substituted phenyl, aromatic or non aromatic 5 or 6 membered heterocyclic ring optionally benzofused; R2 is H or alkyl and the dotted line means an optional bond, for use as medicaments, in particular as antitumor agents.

Description

HETEROCYCLIC COMPOUNDS HAVING ANTITUMOR ACTIVITY

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

The carcinoma of the colon and rectum is a very common tumor in Western countries, in that it has an incidence of about 421,000 new cases each year in the world and is second only to lung and breast tumors as cause of death.

The percentage of patients which can be treated surgically is about 45-50%, the remaining patients being treated with combined chemotherapy, to obtain a complete remission percentage not above 5%.

Tumors of the colon and rectum are usually refractory or poorly sensitive to chemotherapy available at present and the only effective agent to some extent against this type of cancer is 5-fluorouracil .

Unfortunately no therapeutical alternatives exist at present in case of failure of combined chemotherapy substantially based on 5-FU.

Therefore there is a remarkable need for novel drugs active against this type of tumors.

EP-A- 997115391.1, discloses a novel class of compounds with antitumor activity particularly against colon tumors. Said compounds are 4-ureido and thioureido derivatives of 2 (5H) -furanone or 2 (5H) -thiophenone . The present invention relates to novel heterocyclic compounds having 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;

X is selected from the group consisting of —NH-CO-NH-, - H-CO-, -NH-S0₂-, -NH- , -CO-NH-, -CO-NH-NH-, -NH-NH-CO-, -NH-NH-S0₂-, -NH-CO-CO-, -NH-C0-CH₂ - , -NH-NH- , -NH-NH-CO-NH- , -NH-CO-NH-NH-, -CO-, -NH-S0₂-NH-, -CO-NH-CO-NH- , -NH-CO-NH-CO-, -NH-CO-NH-S0₂-, -NH-C (=NH) -NH-NH- ,

-NH-NH-C(=NH) -NH-, -CH=CH- , -CO-CH=CH-, -CH=CH-CO-, cyclopropane-l,2-di-yl, -NH-CH (COOR_c) - ;

R_]_ is selected from the group consisting of hydrogen, C₁_₁₀alkyl_; -(CH₂)_p-A, where in p = 0-4 and A = OH, -NR_aR_b, -COOR_c, -CONR_aR_b, -CONH(CH₂)_q-NR_aR_b, -CONH- (CH₂ ) q-COORc , wherein q = 1-4, R_a and R_b are hydrogen, C]__]_oalkyl , or R_a and R}-,, together with the nitrogen atom they are linked to, form a 4-7 membered heterocyclic ring; Re is hydrogen, alkyl or an alkali or alkaline-earth metal;

R is Cι_-_]_oalkyl, C3 _7cycloalkyl , C₇_₁₄arylalkyl , naphthyl, phenyl optionally mono- or poly- substituted, 5 or 6 membered aromatic or non aromatic heterocyclic ring, optionally benzocondensed;

R is hydrogen or C_]__galkyl; the dotted line means an optional bond; the pure stereoisomers or mixtures thereof and the salts thereof with pharmaceutically acceptable acids or bases, with the provisos that : when Y = 0, n = 0, Rτ_ and R₂ = H, X = -CO-NH- and the dotted line means a bond, R is different from phenyl or mono- or poly- substituted phenyl; when n = 0, Y = O or S, and R₂ = H or Cι__galkyl and the dotted line means a bond, R is different from -NH-CO-NH-; when p = 0, A is different from —OH and from NR_aRj-,; when Y = O, n = 0, Rη_ and R₂ = H and X = -CO-NH-, R is different from a 5 membered aromatic heterocyclic ring containing a nitrogen atom and a sulfur atom, for use as medicaments.

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

US 3 496 187 discloses N-heterocyclic aconamide derivatives of formula

as antibacterials and amebicides. Jpn. J. Cancer Res. (1997), 88 (9), 815-820, describes 5-hydroxy-4- [2-phenyl- (E) -ethenyl] -2 (5H) -furanone as chemopro- tective agent against colon carcinogenesis .

The present invention also relates to novel compounds of formula (I) with the further provisos that: when Y = 0, n = 0, R_λ = H, R₂ = methyl, X = -NH-CO- and the dotted line means a bond, R is different from phenyl and monosubstituted phenyl; - when Y = 0, n = 0, R₂ = H, R_λ = H or CH₂N(CH₃)₂, X = -NH- and the dotted line means a bond, R is different from methyl, phenyl or benzyl ; when Y = O, n = 0, Rτ_ and R₂ = H, X = -CH=CH- and the dotted line means a bond, R is different from 2 , 3 , 6-trimethylphenyl ; when Y = O, n = 0, R_x and R₂ = H, X = -CO- and the dotted line means a bond, R is different from methyl; when Y = 0, n = 0, R_x and R₂ = H, X = -NH-NH- and the dotted line means a bond, R is different from phenyl and p-nitrophenyl ;

The above provisos take into account some known heterocyclic derivatives lacking pharmacological activity, described in the following pubblications .

Chem. Abstracts Vol. 81, 1974, page 3790, 3796x, describes N-arylaconamides as intermediates in the preparation of furoquinolines . The aryl group is a phenyl optionally substituted with one or two methoxy groups.

Aminosubstituted furanone derivatives of formula

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

DE 2 108 926 discloses the preparation of 3-acetyl-4-hydroxy-2 -butenoic acid lactone. Arch. Pharm. (Weinheim) 320, 749-755 (1987) discloses the following compounds: 4- (4-nitrophenylhydrazido) -2 (5H) -furanone and 4-phenylhydrazido-2 (5H) -furanone.

4-Aminofuranone N-acyl derivatives 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 the furanone derivative of formula

as a product from the thermolysis of 6-beta-hydroxy- aplisistatin.

When R is a heterocyclic ring, this 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 poly- substituted phenyl, preferred substituents are Cι__₄alkyl, in particular ethyl, C__3polyhaloalkyl , in particular, trifluoromethyl , and halogen, in particular chlorine.

A preferred group of compounds of formula (I) is the one in which n is 0, Y is NH, Rτ_ and R₂ are hydrogen, R is a substituted phenyl and the dotted line means a bond.

Particularly preferred are the following compounds:

N- (3-chloro-4-ethylphenyl) -N¹ - (5-oxo-2 , 5-dihydro-lH- pyrrol-3-yl) urea

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

Another group of preferred compounds of formula (I) is the one in which n is 0, Y is oxygen, X is -NH-CO-NH-, R is phenyl substituted with one or more groups selected from

C-L_₄alkyl and halogen, Rτ_ is -CH₂-NR_aR_]3, wherein R_a and R_j-- are as defined above and the dotted line is a bond.

Particularly preferred are the following compounds:

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

3-dimethylaminomethyl-4- [N- (4-chlorophenyl) aminocarbo- nylamino] -2 (5H) -furanone

The present invention further relates to pharmaceutical formulations containing a pharmaceutically effective amount of one or more compounds of formula (I) in mixture with pharmaceutically acceptable excipients . Another object of the invention is to provide processes for the preparation of the compounds of formula (I) .

The compounds of formula (I) in which the dotted line means a bond and which have an -NH- group at the 4- position of formula (I) can be prepared by reacting a compound of formula (II)

in which n, Y, Rη_ and R₂ are as defined for compounds o formula (I) , with a compound of formula (III)

W-NH₂ (III) in which W is selected from R, R-NH-CO, R-CO, R-S0₂, R-CO-NH, R-S0₂-NH, R-CO-CO, R-CH₂-CO, R-NH, R-NH-CO-NH, R-NH-NH-CO, R-NH-S0₂, R-CO-NH-CO, R-S0₂-NH-CO, R-NH-NH-C (=NH) , R-NH-C(=NH) -NH, R-CH(COOR_c), wherein R and R_c are as defined 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) under reflux or at 50-150°C, preferably 80- 120°C. The reaction can also be carried out either without solvent or with a small amount of a high boiling solvent, such as toluene, xylene, dioxane, dimethylformamide, nitromethane or n-butanol, if necessary to obtain a clear molten mass. A small amount of a Lewis acid, such as p-toluenesulfonic acid, can be optionally used.

The compounds of formula (I) in which the dotted line means a bond and X is -NH-CO-NH-CO- or -NH-CO-NH-S0₂- are preferably obtained by reacting a compound of formula (II¹)

in which n, Y, Ri and R₂ are as defined for compounds of formula (I), with a compound of formula (III')

W'-N=C=0 (III¹) in which W' is R-CO or R-S0₂, R being as defined for compounds of formula (I) .

The reaction is generally carried out in an inert solvent, such as tetrahydrofuran, dimethoxyethane, dioxane, toluene, xylene, at temperatures ranging from 0°C to the reflux temperature of the solvent, preferably 20-50°C. The compounds of formula (II') in which n = 0 are known products, whose preparation is described for example in Bull. Chem. Soc. Jap. Vol. 60, p. 2139-2150, (1987) and EP 971115391.1. The compounds of formula (II¹) in which n = 1 can be obtained from compounds of formula (II) by treatment with ammonium salts, such as ammonium acetate.

The compounds of formula (III¹) 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, page 2658, (1966) and Ang .

Ch. Vol. 79, page 726, (1967)) and some of them are commercially available.

The compounds of formula I in which the dotted line means a bond and X is -NH-NH-CO- or -NH-NH-S0 - may also be obtained by reaction of a compound of formula (II' ')

in which Y, Rι_ , R₂ , and n are as defined for compounds of formula (I), with a compound of formula (III'¹)

W -Cl (III ' ' ) in which W' is R-CO or R-S0₂, being R as defined for compounds of formula (I) .

The reaction is generally carried out in an inert solvent such as tetrahydrofuran, 1 , 2-dimethoxyethane, dioxane, toluene, xylene, dichloromethane , at a temperature ranging from -20°C to the reflux temperature of the solvent, preferably at 0-40°C, in the presence of at least one molar equivalent of an inorganic or organic base, such as, for example, alkaline or alkaline-earth metal carbonates or bicarbonates , or tertiary amines such as triethylamine or pyridine and the like.

Compounds of formula (II') are known compounds, see for example Arch. Farm., 320, 749-755, 1987. Compounds of formula III ' are well known compounds and most 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 haloacetacetates of formula (IV)

O R- O R₂-CH-C II-CIH-CII-OR₃

Hal (IV)

in which Hal is halogen and R3 is Cη__3al yl, 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 II 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, pages 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 shown 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 means a bond are prepared by reacting a carboxylic acid of formula (V)

in which n, Y, R_]_ and R₂ are as defined for compounds of formula (I) , with a compound of formula (VI)

Z-NH₂ (VI) in which Z is R or R-NH, being R as defined above, through activation of the carboxylic group of the compound of formula

(IV) to condensation, for example by transforming it into a derivative such as acid chloride, hydroxysuccinimmido ester, pentafluophenyl ester or by means of dicyclohexylcarbodii ide . The compounds of formula (I) in which X is -CO- and the dotted line means a bond are prepared by reacting a compound of formula (VII)

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

a) KCN/DMF or 3-benzyl-5- (2-hydroxyethyl) -4-methylthiazo- lium chloride/EtOH b) NBS/CCI₄ c) NaOH

The compounds of formula (I) in which X is -CH=CH- or -CH=CH-CO- and the dotted line means a bond are prepared by reacting a compound of formula (VIII)

in which n, Rτ_ , R₂ and Y are as defined for compounds of formula (I) , with a Wittig reagent R-CH=PPh3 or R-C (=0) CH=PPh3 , then optionally separating the cis and trans isomers by crystallization or chromatography .

The compounds of formula (VII) in which Y = 0 are known (Beilstein, vol. 17, p. 249; Beilstein, vol. 17(3), p. 4300).

The compounds of formula (V) and (VIII) are known in the art (see for example Synthesis 155, 1996) . Alternatively, the above mentioned compounds of formula (I) in which X is -CH=CH- and the dotted line means a bond can be prepared by reacting Wittig reagents of formula (IX) (for example triphenylphosphoranylydenemethyl) -5H-furan-2-one is a compound known from J. Chem. Res. (8) 1985, page 102) or the corresponding Horner-Hemmons reagents of formula (X) (J. Am. Chem. Soc. 1033, 1982), with aldehydes R-CHO, according to the following scheme.

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

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

The compounds of formula (I) in which the dotted line means no 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 R_ is -(CH₂)p-A wherein p = 1 and A = OH or NRaRb can be prepared by reacting compounds of formula (I) in which R_]_ is H with formaldehyde or, respectively, with formaldehyde and an amine of formula R_aR_bNH under Mannich reaction conditions.

The compounds of formula (I) in which R_ is a group of formula [CH₂)_p-A, wherein p is different from 1 and A is different from OH or NR_aR_b, are prepared by reacting dicarbonyl compound of formula (II) in which R]_ is H with a compound of formula T-(CH₂)_p-A, in which T is a leaving group, for example halogen, followed by reaction with a compound of formula W-NH₂ (III), according to the following scheme.

The compounds according to the invention were pharmacologically tested against human tumor cell lines: HT 29 (colon carcinoma) , PC 3 (prostate carcinoma) , H 460M (lung carcinoma) , MCF-7 (breast carcinoma) . Cells were incubated for 144 hour with the tested compound, then cytotoxicity was determined using the MTT test (Mosman, T. "Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay"; J. Immunolog. 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 obtained data showed that the compounds of the present invention have a marked activity against solid tumors, in particular colon tumors.

The compounds of the invention can be administered in doses ranging from 0.01 mg to 0.4 g/Kg body weight daily. A preferred administration procedure is that using a dosage from about 1 mg to about 50 mg/Kg body weight daily, using such unitary doses as to administer in 24 hours from about 70 mg to about 3.5 g of the active substance to a patient of about 70 Kg. Such administration procedure can be adjusted to obtain a better therapeutical effect. For example, doses can be adjusted according to the therapeutical conditions of the patient. The active compounds of the invention can be administered through the oral, intravenous, intramuscular or subcutaneous routes .

The pharmaceutical compositions of the invention contain therapeutically effective amounts of at least one compound of the invention in mixture with excipients compatible with the pharmaceutical use.

The compositions for the oral route generally comprise an inert diluent or an edible carrier and can be in the form of gelatin capsules or tablets. Other possible oral administration forms are capsules, pills, elixirs, suspensions or syrups .

Tablets, pills, capsules and similar compositions can contain the following ingredients (in addition to the active compound) : a ligand, such as microcrystalline cellulose, tragacanth or gelatin; a carrier such as starch or lactose, a disintegrant such as alginic acid, primogel, maize starch and the like; a lubrificant such as magnesium stearate; a fluidifying agent such as colloidal silicon dioxide; a sweetener such as saccharose or saccharin or a flavoring agent such as mint flavor, methyl salicylate or orange flavor. When the selected composition is in the form of capsules, it also can contain a liquid carrier such as a fat oil. Other compositions can 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 used dosages.

For the pharmaceutical compositions for the parenteral administration, the active ingredient can be included in solutions or suspensions, which can further contain the following components: a sterile diluent such as water for injections, saline solution, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterials such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetates, citrates or phosphates and tonicity agents, such as sodium chloride or dextrose. The parenteral preparations can be contained in ampoules, single-dose syringes, glass or plastic vials.

The present invention will be further described by means of the following examples. 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. The resulting thick mixture is added with ethanol (3 ml) and reflux is continued for 16 total hours. The resulting solution is carefully concentrated to dryness and the resulting residue is dissolved in ethanol (5 ml) and acidified with 37% HCl . After 0.5 hours the formed precipitate is recovered by filtration and redissolved in water (15 ml) , removing insolubles while hot. The aqueous solution is adjusted to pH 9 with 20% NaOH and extracted with ethyl acetate (2 x 50 ml) . The combined organic phases are dried and concentrated to dryness, to give a residue which is purified by column chromatography (silica; eluent ethyl acetate) to give 4- (3 -chloro-4 -ethylphenyl) semicarbazide (277 mg) which is used without further purification. Similarly 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-trifluoromethylphenyl ) semicarbazide;

4- (3 -bromophenyl) semicarbazide;

4- (4 -trifluoromethylphenyl) semicarbazide; 4- (4 -methoxyphenyl) semicarbazide ;

4- (3 , 4-dichlorophenyl) semicarbazide;

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

4-(3,5-bis (trifluoromethy1) phenyl) semicarbazide .

Preparation 2 : 4-chlorophenylacetamide A suspension of 4-chlophenylacetic acid (1.7 g) in thionyl chloride (5 ml) is stirred at room temperature for 3 hours. The thionyl chloride excess is distilled off under vacuum, keeping the temperature below 30°C. The residue is taken up into toluene and the solvent is distilled off under vacuum. This operation is repeated three times. After completion, the residue is dissolved in THF (50 mL) and ammonia is bubbled through the solution, keeping the temperature at about 10 °C. The resulting suspension is diluted with water to give a clear solution which is concentrated to 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°C

Similarly are prepared the following products: 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- (trifluoromethyl) phenylacetamide;

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 reacting the suitable benzamides with oxalyl chloride:

3 , 4-dichlorobenzoylisocyanate; 4-chlorobenzoylisocyanate;

4 -bromobenzoylisocyanate ;

4 -trifluoromethylbenzoylisocyanate;

4 -chloro-3 -methylbenzoylisocyanate .

Example 1 : N- (3 -chloro-4 -ethyIphenyl) -N' - (5-oxo-2 , 5-dihydro-lH- pyrrol-3 -yl) urea

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) is refluxed distilling off the ethanol. When all the ethanol is removed, the reaction mixture is added with further absolute ethanol (2 ml) which is again distilled off from the reaction mixture .

The addition of absolute ethanol (2 ml) and its distillation is repeated again. The reaction mixture is evaporated to dryness and the resulting residue is purified by column chromatography (silica; eluent CH₂Cl₂/MeOH 9/1) to give N- (3-chloro-4-ethylphenyl) -N¹ - (5-oxo-2, 5-dihydro-lH-pyrrol-3- yljurea (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, IH) , 7.65 ppm (s, IH) , 9.0 ppm 8s, IH) , 9.33 ppm (s, IH) . Similarly are prepared the following products, using as starting products the suitable commercially available ureas, known or prepared with known methods :

N-phenyl-N' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3-yl) urea, m.p. 225-227°C; N- (4-chlorophenyl) -N¹ - (5-oxo-2 , 5-dihydro-lH-pyrrol-3 - yl) urea;

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

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

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

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

N- (3 -chloro-4 -butylphenyl) -N' - (5-oxo-2 , 5-dihydro-lH- pyrrol -3 -yl ) urea ; N- (4-tert-butyl-3-fluorophenyl) -N' - (5-oxo-2 , 5-dihydro-lH- pyrrol - 3 -yl ) urea ;

N- (4-hydroxyphenyl) -N ' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3 - yl) urea; N- (3-methoxyphenyl) -N' - (5-oxo-2, 5-dihydro-lH-pyrrol-3 - yl) urea;

N- (4-aminophenyl) -N' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3- yl) urea;

N- (4-diethylaminophenyl) -N' - (5-oxo-2 , 5-dihydro-lH-pyrrol- 3-yl)urea;

N- (3-carboxyphenyl) -N¹ - (5-oxo-2 , 5-dihydro-lH-pyrrol-3- yl) urea;

N- (3 -methoxycarbonylphenyl) -N ' - (5-oxo-2 , 5-dihydro-lH- pyrrol -3 -yl ) urea ; N- (4-aminosulfonylphenyl) -N' - (5-oxo-2 , 5-dihydro-lH- pyrrol -3 -yl ) urea ;

N- (4-methanesulfonamidophenyl) -N'- (5-oxo-2 , 5-dihydro-lH- pyrrol -3 -yl ) urea ;

N- (4-tolylsulfonamidophenyl) -N' - (5-oxo-2 , 5-dihydro-lH- pyrrol -3 -yl) urea;

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

N- (2 , 4 -difluorophenyl) -N' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3 - yl) urea; N- (4-ethyl-2-chlorophenyl) -N' - (5-oxo-2, 5-dihydro-lH- pyrrol-3-yl) urea;

N- (isopropyl) -N' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3-yl) urea;

N- (tert-butyl) -N' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3-yl) urea;

N- (octyl) -N¹ - (5-oxo-2 , 5-dihydro-lH-pyrrol-3 -yl) urea; N- (cyclopropyl) -N' - (5-oxo-2 , 5-dihydro- IH-pyrrol -3- yl ) urea ;

N- (cyclohexyl) -N' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3-yl) urea; N- (2-pyridinyl) -N' - (5-oxo-2 , 5-dihydro- lH-pyrrol-3- yl) urea;

N- 1-isoquinolinyl) -N' - (5-oxo-2 , 5-dihydro-lH-pyrrol -3 - yl) urea,

N- 3-quinolinyl) -N' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3 - yl) urea,

N- 3-indolyl) -N' - (5-oxo-2, 5-dihydro-lH-pyrrol-3 -yl) urea;

N- 2-thienyl) -N¹ - (5-oxo-2 , 5-dihydro-lH-pyrrol-3 -yl) urea;

N- 2-pyrrolidinyl) -N' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3- yl) urea j

N- 2-furanyl) -N' - (5-oxo-2, 5-dihydro-lH-pyrrol-3-yl) urea;

N- 2-imidazolyl) -N' - (5-oxo-2, 5-dihydro-lH-pyrrol-3- yl) urea,

N- (2-pyrrolyl) -N ' - (5-oxo-2 , 5-dihydro-lH-pyrrol-3 -yl) urea ,

Example 2 :

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

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 refluxed for one hour azeotropically removing the formed water by means of Dean-Stark. After cooling at room temperature, the resulting precipitate is filtered off and washed thoroughly on the filter with toluene, to give a solid (420 mg) which is suspended in boiling ethanol (10 ml) . After cooling at r.t. the solid is recovered by filtration, to give N- (4-chlorophenyl) -N' - (2-methyl-6-oxo-3 , 6-dihydro-2H-pyran-4- yDurea (385 mg) . m.p. 236-238°C Similarly were obtained the following products by reacting 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 suitable ureas:

N-phenyl-N ' - (2 -methyl-6-oxo-3 , 6-dihydro-2H-pyran-4- yDurea, m.p. 232-233°C;

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

N- (3 -chloro-4 -ethylphenyl) -N¹ - (6-oxo-3 , 6-dihydro-2H- pyran-4-yl) urea; N- (4 -bromophenyl) -N' - (6-oxo-3 , 6-dihydro-2H-pyran-4- yl ) urea ;

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

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

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

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

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

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

N- (3 -chloro-4- ( (2 -methyl) propyl) phenyl) -N' - (6-oxo-3 , 6- dihydro-2H-pyran-4-yl) urea;

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

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

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

N-(3,5-bis (trifluoromethyl) phenyl) -N ' - (6-oxo-3 , 6-dihydro- 2H-pyran-4-yl) urea.

Example 3 :

N- (5-0x0-2 , 5-dihydrofuran-3-yl) -4-chlorobenzamide

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 formed water

(Dean-Stark) . After cooling at room temperature the resulting solid is recrystallized from methanol, then dried under vacuum at 50°C, to obtain 82 mg of N- (5-oxo-2 , 5-dihydrofuran-3-yl) -4- chlorobenzamide . m.p. 260 °C

Similarly are prepared the following products starting from the suitable benzamides :

N- (5-0x0-2 , 5-dihydrofuran-3-yl) benzamide;

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

N- (5-OXO-2 , 5-dihydrofuran-3-yl) -3-chloro-4-ethyl- benzamide;

N- (5-OXO-2 , 5-dihydrofuran-3 -yl) -3 -chloro-4 -propyl- benzamide ;

N- (5-0x0-2 , 5-dihydrofuran-3-yl) -3-chloro-4- ( (2- methyl ) propyl ) benzamide ;

N- (5-0x0-2 , 5-dihydrofuran-3-yl) -3 -chloro-4 -butyl - benzamide;

N- (5-OXO-2 , 5-dihydrofuran-3 -yl) -4 -trifluoromethyl - benzamide;

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 -trifluoromethyl - benzamide;

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-trifluoro- methylbenzamide;

N- (5-OXO-2 , 5-dihydrofuran-3-yl) -3 , 5-bis (trifluoromethyl ) benzamide .

Example 4 :

N- (5-OXO-2, 5-dihydrofura -3 -yl) -4-chlorobenzensulfon- amide.

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

Similarly are prepared the following products starting from the suitable 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 -trifluoromethyl - benzenesulfonamide ; 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-bromobenzenesulfon- amide;

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

N- (5-OXO-2 , 5-dihydrofuran-3-yl) -3 -trifluoromethylben- zenesulfonamide ; N- (5-OXO-2 , 5-dihydrofuran-3 -yl) -4-methoxybenzenesul- fonamide ;

N- (5-OXO-2 , 5-dihydrofuran-3-yl) -3 , 4-dichlorobenzene- sul onamide ;

N- (5-OXO-2 , 5-dihydrofuran-3-yl) -3-chloro-4-trifluo- romethylbenzenesulfonamide .

Example 5 :

4- (3 -chloro-4 -ethyIphenylamino) -5H-furan-2-one

A mixture of 3 -chloro-4-ethylaniline (200 mg) , tetronic acid (128 mg) and traces of p-toluenesulfonic acid monohydrate (1 mg) in toluene (3 ml) is refluxed for 1.5 hours, azeotropically removing the formed water (Dean-Stark) . The mixture is cooled to 40°C and the solid present is filtered off, washed on the filter with toluene and finally recrystallized from methanol, to give 4- (3-chloro-4- ethylphenylamino) -5H-furan-2-one (102 mg) . m.p. 159-160°C

Similarly are prepared the following products by reacting tetronic acid with the suitable 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:

4- (3 -chloro-4-ethylphenylamino) -1, 5-dihydropyrrol-2-one

A suspension of tetramic acid (99 mg) and 3-chloro-4- ethylaniline (186 mg) in toluene (2 ml) is refluxed for 1 hour under nitrogen atmosphere, azeotropically removing the formed water (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 Similarly are prepared the following products by reacting tetramic acid with the suitable anilines:

4- (4-chlorophenylamino) -1 , 5-dihydropyrrol-2 -one;

4 -phenylamino-1 , 5-dihydropyrrol-2-one ;

4- (3-chloro-4-methylphenylamino) -1 , 5-dihydropyrrol-2 -one; 4- (3-chloro-4-propylphenylamino) -1, 5-dihydropyrrol-2-one;

4- (3 -chloro-4- ( (2 -methyl) propylphenylamino) - 1 , 5-dihy- dropyrrol-2 -one ;

4- (3-chloro-4-butylphenylamino) -1 , 5-dihydropyrrol-2-one;

4- (4-bromophenylamino) -1 , 5-dihydropyrrol-2-one; 4- (4 -methylphenylamino) -1 , 5-dihydropyrrol-2-one;

4- (3 -trifluoromethylphenylamino) -1, 5-dihydropyrrol-2-one,-

4- (3-bromophenylamino) -1, 5-dihydropyrrol-2-one;

4- (4 -trifluoromethylphenylamino) -1 , 5-dihydropyrrol-2-one;

4- (4-methoxyphenylamino) -1 , 5-dihydropyrrol-2-one; 4- (3 , 4-dichlorophenylamino) -1 , 5-dihydropyrrol-2-one;

4- (3 -chloro-4 -trifluoromethylphenylamino) -1,5- dihydropyrrol -2 -one ;

4- (3 , 5-bis (trifluoromethyl) phenylamino) -1,5- dihydropyrrol -2 -one . Example 7 :

4- (3 -chloro-4-ethylphenylamino) -5H-thiophen-2-one

A mixture of 4-hydroxy-5H-thiophen-2-one (thiotetronic acid; 232 mg) , 3-chloro-4-ethylaniline (311 mg) and traces of p-toluenesulfonic acid monohydrate (2 mg) in toluene (2 ml) is refluxed for 30 minutes, azeotropically removing the formed water (Dean-Stark) . After cooling at room temperature, the resulting solid is filtered off and washed with ethyl acetate, to give 4- (3-chloro-4-ethylphenylamino) -5H-thiophen-2-one (300 mg) . m.p. 186-187°C

Similarly are prepared the following products by reacting 4-hydroxy-5H-thiophen-2-one with the suitable anilines:

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

4 -phenylamino-5H-1hiophen-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 -butyIphenylamino) -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 :

N' - (5-OXO-2, 5-dihydrofuran-3-yl) -4-chlorobenzoylhydra- zide

Under nitrogen atmosphere, a mixture of N-(4- chlorobenzoyl) hydrazine (341 mg) , tetronic acid (200 mg) and traces of p-toluenesulfonic acid (1 mg) in toluene (3 ml) is refluxed with stirring for 2 hours. After cooling at 40°C, the resulting solid is filtered off 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 :

N' - (5-OXO-2, 5-dihydrofuran-3-yl) -3 -chloro-4 -methy1- benzoylhydrazide

A suspension of 3 -chloro-4 -methylbenzoic acid (0.5 g) in thionyl chloride (3 ml) is heated at 50°C for two hours. The resulting solution is concentrated to dryness and the residue is taken up into n-heptane and concentrated to dryness again. This operation is repeated twice. The resulting oily residue is redissolved in tetrahydrofuran and dropped into 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 resulting red suspension is stirred at room temperature for 2 h and subsequently poured into a NaH₂PU4 20% solution (100 ml) . After extraction with ethyl acetate (3x100 ml) the combined organic phases are dried over Na₂Sθ4 and evaporated to dryness. The resulting residue is crystallized from ethyl acetate, to give N ' - (5-oxo-2 , 5-dihydrofuran-3 -yl) -3-chloro-4- methylbenzoylhydrazide (312 mg) . m.p. 211-213°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) benzoylhydrazide, m.p. 224-226°C N' - (5-OXO-2 , 5-dihydrofuran-3-yl) -4-trifluorobenzoylhy- drazide;

N' - (5-OXO-2 , 5-dihydrofuran-3-yl) -2-bromobenzoylhydra- zide;

N¹ - (5-OXO-2 , 5-dihydrofuran-3-yl) -3 -bromobenzoylhydrazi- de;

N¹ - (5-0x0-2 , 5-dihydrofuran-3-yl) -4-bromobenzoylhydrazi- de;

N' - (5-OXO-2 , 5-dihydrofuran-3-yl) -4-methylbenzoylhydra- zide; N¹ - (5-OXO-2 , 5-dihydrofuran-3-yl) -3 -trifluoromethylben- zoylhydrazide ;

N' - (5-OXO-2 , 5-dihydrofuran-3-yl) -4-methoxybenzoylhydra- zide; ' - (5-OXO-2 , 5-dihydrofuran-3 -yl) -3 , 4-dichlorobenzoylhy- drazide;

N¹ - (5-OXO-2 , 5-dihydrofuran-3-yl) -3 -chloro-4 -trifluoro- methylbenzoylhydrazide ;

N' - (5-OXO-2 , 5-dihydrofuran-3-yl) -3 , 5-bis (trifluoromethyl ) benzoylhydrazide .

Example 10:

N' - (5-OXO-2, 5-dihydrofuran-3-yl) -4-chlorobenzenesulfo- nylhydrazide

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 at 0°C. After that, the reaction mixture is warmed to room temperature and after 1.5 hours is concentrated to dryness. The resulting residue is taken up in water and stirred for 1 hour at room temperature. The filtered off solid is resuspended in hot 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 is treated in ethyl ether, to give N' - (5-oxo-2 , 5-dihydrofuran-3- yl) -4-chlorobenzenesulfonylhydrazide (418 mg) . m.p. 224-226°C Similarly are prepared the following products by reacting 4-hydrazino-5H-furan-2-one with the suitable sulfonyl chlorides :

N' - (5-OXO-2 , 5-dihydrofuran-3-yl) benzenesulfonylhydra- zide, m.p. 208-209°C N' - (5-0x0-2 , 5-dihydrofuran-3-yl) -4 -trifluorobenzenesul- fonylhydrazide ;

N¹ - (5-OXO-2 , 5-dihydrofuran-3-yl) -2 -bromobenzenesul- fonyldrazide; N' - (5-OXO-2 , 5-dihydrofuran-3-yl) -3-bromobenzenesul- fonyldrazide ;

N' - (5-oxo-2 , 5-dihydrofuran-3-yl) -4 -bromobenzenesul- fonylhydrazide ;

N' - (5-OXO-2 , 5-dihydrofuran-3-yl) -4-methylbenzenesul- fonylhydrazide;

N ' - (5-oxo-2 , 5-dihydrofuran-3-yl) -3 -trifluoromethy1- benzenesulfonylhydrazide ;

N ' - (5-oxo-2 , 5-dihydrofuran-3 -yl) -4-methoxybenzenesul- fonylhydrazide ; N ' - (5-oxo-2 , 5-dihydrofuran-3-yl ) -3 , 4-dichlorobenzene- sulfonylhydrazide ;

N' - (5-0x0-2 , 5-dihydrofuran-3-yl) -3 -chloro-4 -trifluoromethylbenzenesulfonylhydrazide ;

N' - (5-OXO-2 , 5-dihydrofuran-3-yl) -3 , 5 -bis (trifluorome- thyl) benzenesulfonylhydrazide .

Example 11:

N- (3 -chloro-4 -methylphenyl) -N' - (5-oxo-2 , 5-dihydrofuran-3 ■ yl) hydrazine

A solution of 3 -chloro-4 -methylphenylhydrazine (350 mg) in ethanol (20 ml) , heated at 50°C, is added dropwise with a solution of tetronic acid (220 mg) in water (15 ml) . After completion of the addition, the reaction mixture is refluxed for two hours and subsequently concentrated to dryness. The resulting residue 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 are prepared the following products by reacting tetronic aci with the suitable hydrazines :

N-phenyl-N' - (5-oxo-2 , 5-dihydrofuran-3 -yl) hydrazine, m.p . 105-107°C;

N- (4-chlorophenyl) -N' - (5-oxo-2 , 5-dihydrofuran-3 - yDhydrazine, m.p. 154-156°C;

N- (4-nitrophenyl) -N' - (5-oxo-2 , 5-dihydrofuran-3 - yDhydrazine, m.p. 218-220°C; N- (4 -bromophenyl) -N ' - (5-oxo-2 , 5-dihydrofuran-3 - yl) hydrazine;

N- (4 -methylphenyl) -N' - (5-oxo-2 , 5-dihydrofuran-3 - yl) hydrazine;

N- (3 -trifluoromethylphenyl) -N' - (5-oxo-2 , 5-dihy-drofuran- 3 -yl) hydrazine;

N- (3 -bromophenyl) -N' - (5-oxo-2 , 5-dihydrofuran-3 - yl) hydrazine;

N- (4-trifluoromethylphenyl) -N' - (5-oxo-2 , 5-dihy-drofuran- 3 -yl ) hydrazine ; N- (4-methoxyphenyl) -N' - (5-oxo-2 , 5-dihydrofuran-3 - yl) hydrazine;

N- (3 , 4-dichlorophenyl) -N' - (5-oxo-2 , 5-dihydrofuran-3 - yl) hydrazine;

N- (3 -chloro-4 -trifluoromethylphenyl) -N¹ - (5-oxo-2 , 5- dihydrofuran- 3 -yl) hydrazine ;

N- (3 , 5-bis (trifluoromethyl) phenyl) -N' - (5-oxo-2 , 5- dihydrofuran-3 -yl ) hydrazine . Example 12 :

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

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, azeotropically removing the formed water (Dean-Stark) . After that, the reaction mixture is added with methanol (10 ml) and reflux is continued for a further 0.5 hours. After cooling at room temperature, the formed precipitate is filtered off, to give 1- (5-oxo-2 , 5- dihydrofuran-3-yl) -4- (4-chlorophenyl) semicarbazide (162 mg) . m.p. 229-231°C

Similarly 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- methyl) 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- (5-0x0-2 , 5-dihydrofuran-3-yl) -4- (4 -methylphenyl) semicarbazide; 1- (5-OXO-2 , 5-dihydrofuran-3-yl) -4- (3-trifluoromethylphenyl) semicarbazide;

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

1- (5-OXO-2 , 5-dihydrofuran-3-yl) -4- (4 -trifluoromethyl - phenyl) semicarbazide ;

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

1- (5-OXO-2 , 5-dihydrofuran-3-yl) -4- (3 , 4-dichlorophe- nyl) semicarbazide; 1- (5-OXO-2 , 5-dihydrofuran-3-yl) -4- (3-chloro-4- trifluoromethylphenyl) semicarbazide;

1- (5-0x0-2 , 5-dihydrofuran-3-yl) -4- (3 , 5-bis (trifluoromethyl) phenyl) semicarbazide .

Example 13 : 4- (5-oxo-2 , 5-dihydrofuran-3-yl) -1-phenylsemicarbazide

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 an hour, azeotropically removing the formed water (Dean- Stark) . After cooling at room temperature, toluene is decanted off and the solid residue is taken up in hot methanol (20 ml) while stirring for two hours. The solid is filtered off (1.02 g) and redissolved in boiling methanol (60 ml) , filtering off the undissolved portion while hot. By concentration of the methanol solution to about 30 ml, 4- (5-oxo-2 , 5-dihydrofuran- 3- yl) -1-phenylsemicarbazide (0.76 g) crystallizes. m.p. 221-223°C

Example 14 :

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

A stirred mixture of 4-chlorophenylacetamide (170 mg) , tetronic acid (100 mg) and traces of p-toluenesulfonic acid (1 mg) in anhydrous toluene (2 ml) is refluxed for an hour under nitrogen atmosphere, azeotropically removing the formed water

(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 small volume and the separated solid is filtered off, to give N- (5-oxo-2 , 5-dihydrofuran-3- yl) -4-chlorophenylacetamide (30 mg) . m.p. 161-162°C

Similarly are prepared:

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-dichlorophenyl- acetamide;

N- (5-0x0-2 , 5-dihydrofuran-3-yl) -3 , 5-bis (trifluoromethyl ) phenylacetamide ;

N- (5-OXO-2 , 5-dihydrofuran-3-yl) - 1 -naphthylacetamide ; N- (5-0x0-2 , 5-dihydrofuran-3-yl) -2 -naphthylacetamide ;

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

N- (5-OXO-2 , 5-dihydrofuran-3-yl) -2 -fluorophenylacetamide ;

N- (5-OXO-2 , 5-dihydrofuran-3 -yl ) -2 -chlorophenylacetamide;

N- (5-0x0-2 , 5-dihydrofuran-3-yl) -2 , 4 -dichlorophenyl - acetamide;

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:

Ethyl DL-2- (5-oxo-2, 5-dihydrofuran-3-ylamino) -4- chlorophenylpropionate

A stirred suspension of DL-4-chlorophenylalanine ethyl ester (1.27 g; obtained by neutralization of the corresponding hydrochloride with a sodium bicarbonate saturated solution and subsequent extraction with ethyl acetate), tetronic acid (0.55 g) and traces of p-toluenesulfonic acid (5 mg) in toluene (30 ml) is refluxed for two hours, azeotropically removing the formed water (Dean-Stark) . After cooling at 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 treatment with ethyl ether, to give ethyl DL-2- (5-oxo-2 , 5-dihydrofuran-3-ylamino) -4-chloro- phenylpropionate (544 mg) . m.p. 127-129°C.

Similarly are prepared:

Ethyl DL-2- (5-oxo-2 , 5-dihydrofuran-3-ylamino) phenyl - propionate;

Ethyl DL-2- (5-oxo-2 , 5-dihydrofuran-3-ylamino) -4- hydroxyphenylpropionate;

Methyl DL-2- (5-oxo-2 , 5-dihydrofuran-3-ylamino) -4- bromophenylpropionate ;

Methyl DL-2- (5-oxo-2 , 5-dihydrofuran-3-ylamino) -4- fluorophenylpropionate ; Ethyl DL-2- (5-OXO-2 , 5-dihydrofuran-3-ylamino) -4- nitrophenylpropionate .

Example 16:

DL-2- (5-0x0-2, 5-dihydrofuran-3-ylamino) -4-chloro- phenylpropionic acid

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 small volume and acidified to pH 2 with hydrochloric acid. The separated precipitate is stirred for 12 hours, then filtered off and washed on the filter with water. After drying at 50°C under vacuum overnight, DL-2- (5-oxo-2 , 5-dihydrofuran-3- ylamino) -4-chlorophenylpropionic acid is obtained (307 mg) . m . p . 218 - 220 ° C .

Similarly are prepared:

DL-2- (5-OXO-2 , 5-dihydrofuran-3-ylamino) phenylpropionic acid; DL-2- (5-0x0-2 , 5-dihydrofuran-3 -ylamino) -4-hydroxyphe- nylpropionic acid;

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

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

DL-2- (5-0x0-2 , 5-dihydrofuran-3 -ylamino) -4-nitrophe- nylpropionic acid.

Example 17: l-Benzoyl-3 - (5-oxo-2 , 5-dihydrofuran-3 -yl) -urea

A suspension of 4-amino-5H-furan-2-one (obtained by condensing tetronic acid with ammonium acetate see EP 97115391.1; 500 mg) in anhydrous THF (25 ml) is added with sodium hydride (60% suspension in mineral oil; 110 mg) and the resulting suspension is heated to 40 °C for two hours. After cooling at room temperature, benzoylisocyanate (735 mg) is added and stirring at room temperature is continued for 18 hours. The reaction mixture is added with methanol and evaporated to dryness. The residue is taken up into a small volume of an ethyl acetate and water mixture slightly acidified with NaH₂P04- The solid insoluble in the two phases is filtered off, washed on the filter with water and some ethyl acetate and subsequently recrystallized from methanol, to give l-benzoyl-3- (5-oxo-2 , 5-dihydrofuran-3-yl) urea (120 mg) . m.p. 227-230 °C (dec.) Similarly are prepared the following compounds:

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

1- (4-chlorobenzoyl) -3- (5-oxo-2 , 5-dihydrofuran-3-yl) urea (m.p. 230°C with decomposition);

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

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

1- (4-chloro-3-methylbenzoyl) -3- (5-oxo-2 , 5-dihydrofuran-3- yDurea, m.p. 199-204 °C.

Example 18 :

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

In a partial solution of 4 -amino-5H- furan-2 -one (obtained by condensing tetronic acid with ammonium acetate; 100 mg) in 1 , 2-dimethoxyethane (5 ml) is dropped a solution of 4-methylsulfonylisocyanate (197 mg) in 1 , 2-dimethoxyethane (2 ml), cooling at 5°C. The suspension is stirred at 5°C for an hour, then at room temperature for 24 hours. The formed precipitate is filtered off to give 1- (4-methylsulfonyl) -3- (5- oxo-2 , 5-dihydrofuran-3-yl) urea . m.p. 226°C with decomposition. Similarly are prepared:

1- (4-chlorophenylsulfonyl) -3- (5 -oxo-2 , 5-dihydrofuran-3 - yl)urea (m.p. 235°C with decomposition); l-phenylsulfonyl-3- (5-oxo-2 , 5-dihydrofuran-3 -yl) urea, m.p. 189-190 °C. Example 19 :

N- (4 -Chlorophenyl) -N' - (5-oxo-4-dimethylaminomethyl-2 , 5- dihydrofuran-3-yl)urea

A suspension of N- (4-chlorophenyl) -N' - (5-oxo-2 , 5-dihydro- furan-3 -yl) urea (EP97115391.1 ; 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 refluxed for two hours. The resulting solution is cooled to room temperature, 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 small volume. The resulting precipitate is filtered off and dried under vacuum at 50 °C for an 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 added with a 1 N solution of HCl in ethyl ether (3.8 ml) . The suspension is stirred at room temperature for two hours. The precipitate is filtered off to give N- (4-chlorophenyl) -N' - (5-oxo-4-dimethylaminomethyl-2 , 5- dihydro- furan-3 -yl) urea hydrochloride (156 mg) . m.p. 250-253.

Similarly are prepared the following compounds, by reacting the N- (5-oxo-2 , 5-dihydrofuran-3 -yl) ureido derivatives described in EP97115391.1 (5/9/1997) with formaldehyde and the suitable amines:

N-phenyl-N' - (5-oxo-4- (4 ' -morpholino) methyl -2 , 5-dihydro- furan-3-yl)urea hydrochloride, m.p. 226-228°C;

N-phenyl-N' - ( 5 -oxo-4 -dimethylaminomethyl-2 , 5- dihydrofuran-3-yl) urea hydrochloride, m.p. 225-228°C;

N- (3-chloro-4-ethylphenyl) -N' - (5-oxo-4- dimethylaminomethyl-2 , 5 -dihydrofuran-3 -yl) urea hydrochloride, m.p. 230-232°C;

N- (4-chlorophenyl) -N' - (5 -oxo-4- (4 ' -morpholino) methyl-2, 5- dihydrofuran-3-yl) urea;

N- (4 -fluorophenyl) -N' - (5-oxo-4- (4 ' -morpholino) methyl-2 , 5- dihydrofuran-3 -yl) urea;

N- (4-chloro-3-ethylphenyl) -N' - (5-oxo-4- (1 ' -piperi- dino) methyl-2 , 5 -dihydrofuran-3 -yl) urea;

N- (3-chloro-4-methylphenyl) -N¹ - (5-oxo-4-dimethyl- aminomethyl-2 , 5-dihydrofuran-3-yl) urea; N- (3-chloro-4-propylphenyl) -N' - (5-oxo-4-dimethylamino- methyl-2 , 5-dihydrofuran-3 -yl) urea;

N- (3-chloro-4- ( (2 -methyl) propyl) phenyl) -N' - (5-oxo-4- dimethylaminomethyl-2 , 5 -dihydrofuran-3 -yl) urea;

N- (3 -chloro-4 -butylphenyl) -N' - (5-oxo-4- (1 ' -piperidi- no) methyl-2 , 5 -dihydrofuran-3 -yl) urea;

N- (4-tert-butyl-3-fluorophenyl) -N' - (5-oxo-4- (1 ' - piperidino) methyl-2 , 5 -dihydrofuran-3 -yl) urea;

N- (3-methoxyphenyl) -N' - (5-oxo-4- (1 ' -pyrrolidino) methyl - 2 , 5 -dihydrofuran-3 -yl) urea; N- (4-diethylaminophenyl) -N' - (5 -oxo-4- (1 ' -piperidino) methyl-2, 5 -dihydrofuran-3 -yl) urea;

N- (3 -carboxyphenyl) -N' - (5 -oxo-4 -dimethylaminomethyl-2 , 5- dihydrofuran-3 -yl ) urea ;

N- (3-methoxycarbonylphenyl) -N' - (5-oxo-4-dimethylamino- methyl-2 , 5 -dihydrofuran-3 -yl) urea;

N- (2 -fluorophenyl) -N' - (5-oxo-4-dimethylaminomethyl-2 , 5- dihydrofuran-3 -yl ) urea ;

N- (2 , 4 -difluorophenyl) -N¹ - (5 -oxo-4- (4 ' -morpholino) me- thyl-2 , 5-dihydrofuran-3 -yl) urea;

N- (4 -ethyl -2 -chlorophenyl) -N' - (5-oxo-4- (4 ' -morpholino) methyl-2 , 5-dihydrofuran-3 -yl) urea;

N- (isopropyl) -N' - (5 -oxo-4- (4 ' -morpholino) methyl-2, 5- dihydrofuran-3 -yl) urea;

N- (tert-butyl) -N' - (5-oxo-4 -dimethylaminomethyl-2 , 5- dihydrofuran-3-yl) urea;

N- (octyl) -N' - (5-OXO-4- (1 ' -piperidino) methyl-2 , 5-dihydro- furan-3 -yl) urea; N- (cyclopropyl) -N' - (5 -oxo-4 -dimethylaminomethyl-2 , 5- dihydrofuran-3-yl) urea;

N- (cyclohexyl) -N ' - (5-oxo-4- (4 ' -morpholino) methyl-2 , 5- dihydrofuran-3-yl) urea ;

N- (2-pyridinyl) -N' - (5 -oxo-4- (1 ' -piperidino) methyl-2 , 5- dihydrofuran-3 -yl) urea;

N- (1-isoquinolinyl) -N' - (5 -oxo-4 -dimethylaminomethyl-2 , 5- dihydrofuran-3-yl) urea;

N- (3-quinolinyl) -N' - (5-oxo-4-dimethylaminomethyl-2 , 5- dihydrofuran-3 -yl) urea ; N- (2-thienyl) -N' - (5 -oxo-4 -dimethylaminomethyl-2 , 5- dihydrofuran-3-yl) urea;

N- (2 -pyrrolidinyl) -N' - (5 -oxo-4- (4 ' -morpholino) methyl-2 , 5- dihydrofuran-3 -yl) urea;

N- (2-furanyl) -N' - (5-oxo-4- (4 ' -morpholino) methyl-2 , 5- dihydrofuran-3 -yl) urea;

N- (2-imidazolyl) -N' - (5 -oxo-4- (1 ' -piperidino) methyl-2 , 5- dihydrofuran-3-yl) urea;

N- (2-pyrrolyl) -N' - (5-oxo-4- (1 ' -piperidino) methyl-2 , 5- dihydrofuran-3 -yl ) urea . Example 20 :

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

A solution of 4- (triphenylphosphoranylydenemethyl) -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 dry methylene chloride (6 ml) is heated under mild reflux for three hours under nitrogen atmosphere. The reaction mixture is concentrated to dryness and the resulting residue is treated with tert-butyl methyl ether (10 ml) under stirring for two hours. The solid is filtered off and purified by column chromatography (silica; eluent: hexane/ethyl acetate 1/1) . The mother liquors from the treatment with tert-butyl methyl ether are concentrated to dryness, then purified by column chromatography, using the same conditions as above. The fractions containing the product from the two chromatographic purifications are combined and concentrated to dryness, to give a waxy solid (175 mg) which is treated with isopropyl ether under stirring for two hours. The solid is filtered off to give 4- (3 , 4 , 5-trimethoxystyryl) -5H-furan-2-one (103 mg) as mixture of the E and Z isomers. m.p. 106-108°C.

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

4- (3 , 4-dimethoxystyryl) -5H-furan-2-one; 4- (4-methoxystyryl) -5H-furan-2 -one; 4-styryl-5H-furan-2-one;

4- (4-chlorostyryl) -5H-furan-2 -one, m.p. 164-166°C. Example 21 :

E-4- (4-chlorostyryl) -5H-furan-"2-one

A solution of 4- (triphenylphosphoranylydenemethyl) -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 dry methylene chloride (16 ml) is heated under .mild reflux for three hours under nitrogen atmosphere. The reaction mixture is concentrated to dryness and the resulting residue 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 E and Z isomeric mixture (370 mg) . By treatment of this mixture with ethyl acetate and filtration,

4- (4 -chlorostyryl) -5H-furan-2-one is recovered as the pure E isomer (190 mg) . m.p. 198-200°C.

Similarly are prepared the following products as pure geometric isomers :

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

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

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

Z-4- (3 -chloro-4 -trifluoromethylstyryl) -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

1. 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-, -NH-, -CO-NH-, -CO-NH-NH-, -NH-NH-CO-, -NH-NH-S0₂-, -NH-CO-CO-, -NH-CO-CH₂-, -NH-NH-, -NH-NH-CO-NH- , -NH-CO-NH-NH-, -CO-, -NH-S0₂-NH-, -CO-NH-CO-NH- , -NH-CO-NH-CO-, -NH-CO-NH-S0₂-, -NH-C (=NH) -NH-NH- ,

-NH-NH-C(=NH) -NH-, -CH=CH-, -CO-CH=CH-, -CH=CH-CO-, cyclopropane- 1, 2-di-yl, -NH-CH (COOR_c) - ;

R_ is selected from the group consisting of hydrogen, C₁_₁₀alkyl, -(CH₂)_p-A, wherein p = 0-4 and A = OH, -NR_aR_b, -COOR_c, -CONR_aR_b, -CONH(CH₂)_g-NR_aR_b, -CONH- (CH₂ ) _g-COOR_c , wherein q = 1-4, R_a and R_b are hydrogen, C_j___o^alkyl , or R_a and R_b, together with the nitrogen atom they are linked to, form a 4-7 membered heterocyclic ring; R_c is hydrogen, alkyl or an alkali or alkaline-earth metal;

R is C_]__ι_o^lkyl , C3 _7cycloalkyl , C7_ ^arylalkyl , naphthyl, phenyl optionally mono- or poly- substituted, 5 or 6 membered aromatic or non aromatic heterocyclic ring, optionally benzocondensed; - R₂ is hydrogen or C .galkyl; the dotted line means an optional bond; the pure stereoisomers or mixtures thereof and the salts thereof with pharmaceutically acceptable acids or bases, with the provisos that: when Y = 0, n = 0, Rj_ and R₂ = H, X = -CO-NH- and the dotted line means a bond, R is different from phenyl or mono- or poly- substituted phenyl; - when n = 0, Y = O or S, R₁ and R₂ = H or Cι__galkyl and the dotted line means a bond, R is different from —NH-CO-NH-; when p = 0, A is different from —OH and from NR_aR_b; when Y = 0, n = 0, R_λ and R₂ = H and X = -CO-NH- , R is different from a 5 membered aromatic heterocyclic ring containing a nitrogen atom and a sulfur atom, for use as medicaments.

2. Compounds as claimed in 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-C0-NH-,

-NH-CO-, NH-S0₂-, -NH-, -CO-NH-, -C0-NH-NH-, -NH-NH-CO-, -NH-NH-S0₂-, -NH-CO-CO-, -NH-C0-CH₂-, -NH-NH-, -NH-NH-CO-NH- ,

-NH-CO-NH-NH-, -CO-, -NH-S0₂-NH-, -CO-NH-CO-NH- , -NH-CO-NH-CO- ,

-NH-CO-NH-S0₂-, -NH-C(=NH) -NH-NH-, -NH-NH-C (=NH) -NH- , -CH=CH-,

-CO-CH=CH-, -CH=CH-CO-, cyclopropane- 1 , 2 -di-yl , -NH-CH (COOR_c) - ;

Rτ_ is selected from the group consisting of hydrogen, C₁_₁₀alkyl, -_.(CH₂)_p-A, wherein p = 0-4 and A = OH, -NR^^,

-COOR_c, -CONR_aR_b, -CONH(CH₂)_q-NR_aR_b, -CONH- (CH₂ ) q-COOR_c , wherein q = 1-4, R_a and R_b are hydrogen, Cι__ιo^alkyl , or R_a and

R_b, together with the nitrogen atom they are linked to, form a 4-7 membered heterocyclic ring; R_c is hydrogen, alkyl or an alkali or alkaline-earth metal;

R is C]__ι_oalkyl, C₃ _₇cycloalkyl , C₇_^arylalkyl , naphthyl, phenyl optionally mono- or poly- substituted, 5 or 6 membered aromatic or non aromatic heterocyclic ring, optionally benzocondensed;

R₂ is hydrogen or C^-galkyl; the dotted line means an optional bond; the pure stereoisomers or mixtures thereof and the salts thereof with pharmaceutically acceptable acids or bases, with the provisos that: when Y = 0, n = 0, R_λ and R₂ = H, X = -CO-NH- and the dotted line means a bond, R is different from phenyl or mono- or poly- substituted phenyl; - when Y = 0, n = 0 , R₁ = H, R₂ = methyl, X = -NH-CO- and the dotted line means a bond, R is different from phenyl and monosubstituted phenyl; when Y = 0, n = 0, R₂ = H, R_λ = H or CH₂N(CH₃)₂, X = -NH- and the dotted line means a bond, R is different from methyl, phenyl or benzyl; when Y = 0, n = 0, R₁ and R₂ = H, X = -CH=CH- and the dotted line means a bond, R is different from 2,3,6- trimethylphenyl ; when Y = 0, n = 0, R_λ and R₂ = H, X = -CO- and the dotted line means a bond, R is different from methyl; when Y = O, n = 0, Rι_ and R₂ = H, X = -NH-NH- and the dotted line means a bond, R is different from phenyl and p-nitrophenyl ; when n = 0, Y = O or S, R]_ and R₂ = H or C^.galkyl and the dotted line means a bond, R is different from —NH-CO-NH-; when p = 0, A is different from —OH and from NR_aR]-.; when Y = 0, n = 0, R]_ and R₂ = H and Y = -CO-NH-, R is different from a 5 membered aromatic heterocyclic ring containing a nitrogen atom and a sulfur atom.

4. Compounds as claimed in claim 3, in which 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 as claimed in claim 3 , in which R is a phenyl substituted with one or more groups selected from Cι__4alkyl, Cτ_._3polyhaloalkyl and halogen.

6. Compounds as claimed in claim 5, in which R is a phenyl substituted with one or more groups selected from ethyl, trifluoromethyl and chlorine.

7. Compounds as claimed in claim 3, in which n is 0, Y is NH, X is -NH-C0-NH-, R^_, and R₂ are hydrogen, R is a phenyl substituted and the dotted line means a bond.

8. Compounds as claimed in claim 7, having the following structures :

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

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

9. Compounds as claimed in claim 3, in which n is 0, Y is oxygen, X is -NH-CO-NH-, R is phenyl having one or more substituents selected from C_j__4alkyl and halogen, Rη_^ is -CH₂-NR_aR_b, wherein R_a and R_b are defined as in claim 1 and the dotted line means a bond.

10. Compounds as claimed in 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.

11. A process for the preparation of a compound of formula (I) as claimed in claim 1, which comprises reacting a compound of formula (II)

in which Y, Rτ_ and R₂ have the same meanings as in compounds of formula (I), with a compound of formula (III)

W-NH₂ (III) in which W is selected from R, R-NH-CO, R-CO, R-S0₂, R-CO-NH, R-S0₂-NH, R-CO-CO, R-CH₂-CO, R-NH, R-NH-CO-NH, R-NH-NH-CO, R-NH-S0₂, R-CO-NH-CO, R-S0₂-NH-CO, R-NH-NH-C (=NH) , R-NH-C(=NH) -NH, R-CH(COOR_c), wherein R and R_c have the same meanings as in compounds of formula (I) .

12. A process as claimed in claim 11 in which said reaction is carried out in solution at the reflux temperature, optionally in the presence of a Lewis acid.

13. A process as claimed in claim 12 in which said reaction is carried out at 80-120°C.

14. A process as claimed in claim 11, in which said reaction is carried out without a solvent, optionally in the presence of a Lewis acid.

15. A process for the preparation of a compound of formula

(I) as claimed in claim 1, in which X is -NH-CO-NH-CO- or

-NH-CO-NH-S0₂- , which comprises reacting a compound of formula

(II')

in which n, Y, R_ and R₂ are as defined in claim 1, with a compound of formula (III')

W'-N=C=0 (III¹) in which W¹ is R-CO or R-S0₂, and R has the same meanings as in claim 1.

16. A process as claimed in claim 15, in which said reaction is carried out in an inert solvent at temperatures ranging from 0°C to the reflux temperature of the solvent, preferably from 20 to 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. The use of a compound of 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-C0-, -NH-S0₂-, -NH-, -CO-NH-, -CO-NH-NH-, -NH-NH-CO-, -NH-NH-S0₂-, -NH-CO-CO-, -NH-C0-CH₂-, -NH-NH-, -NH-NH-CO-NH- , -NH-CO-NH-NH-, -CO-, -NH-S0₂-NH-, -CO-NH-CO-NH- , -NH-CO-NH-CO- ,

-NH-CO-NH-S0₂-, -NH-C(=NH) -NH-NH-, -NH-NH-C (=NH) -NH- , -CH=CH-,

-CO-CH=CH-, -CH=CH-CO-, cyclopropane-1, 2 -di-yl, -NH-CH (COOR_c) - ;

R_]_ is selected from the group consisting of hydrogen,

C₁_₁₀alkyl, -(CH₂)_p-A, wherein p = 0-4 and A = OH, -NR_aR_b, -COOR_c, -CONR_aR_b, -CONH (CH₂ ) _g-NR_aR_b, -CONH- (CH₂ ) _q-COOR_c , wherein q = 1-4, R_a and R_b are hydrogen, Cτ___]__Qal yl , or R_a and R_b, together with the nitrogen atom they are linked to, form a 4-7 membered heterocyclic ring; R_c is hydrogen, alkyl or an alkali or alkaline-earth metal;

R is Cι_ιo^al^yl' C3_7cycloalkyl, C _^arylalkyl , naphthyl, phenyl optionally mono- or poly- substituted, 5 or 6 membered aromatic or non aromatic heterocyclic ring, optionally benzocondensed;

R₂ is hydrogen or Cι_galkyl ; the dotted line means an optional bond; the pure stereoisomers or mixtures thereof and the salts thereof with pharmaceutically acceptable acids or bases, with the provisos that: when n = 0, Y =.O or S, R₁ and R₂ = H .or C₁_₆alkyl and the dotted line means a bond, R is different from —NH-CO-NH-; when p = 0, A is different from —OH and NR_aR_b, for manufacturing a medicament with anticancer activity.