NZ308123A - Substituted tetrahydropyrano[3,2-d]oxazolones and medicaments - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 308123 New Zealand No. International No. 308123 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 27.04.1995; Complete Specification Filed: 24.04.1996 Classification:^) C07D498/04.20; A61K31/42 Publication date: 28 July 1998 Journal No.: 1430 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Novel substituted tetrahydropyrano[3,2-d]oxazolones, method for their preparation and pharmaceutical compositions containing them Name, address and nationality of applicant(s) as in international application form: ADIR ET COMPAGNIE, 1 rue Carle Hebert, 92415 Courbevoie Cedex, France 3081; PCT/FR9 6/00629 new substituted tetrahydropyrano[3,2 -d]oxazolones# process for preparing them and pharmaceutical compositions containing them The present invention relates to new compounds having a tetrahydropyrano[3,2-d]oxazolone structure, to a process for preparing them and to the pharmaceutical compositions containing them. The compounds or the present invention find an entirely advantageous 10 therapeutic use by virtue of their angiogenesis-inhibiting power.

Angiogenesis (or neovascularization) is defined as the development and growth of new capillary blood vessels. The process of angiogenesis is essential in 15 many physiological situations including the development of the embryo, the normal cicatrization of wounds and the development of the endometrium after menstruation. Beyond these situations, angiogenesis is very rare in normal adults and the mitosis of the endothelial cells 20 which generates the walls of the blood vessels is very slow, with cell renewal times measured in years.

Abnormal angiogenesis (that is to say stimulation of the growth of new blood vessels due to a pathological syndrome) is an established characteristic 25 for many diseases, in particular diabetic retinopathy, rheumatoid arthritis, hemangiomas and the growth of solid tumors. Angiogenesis may also play an important part in other diseases such as arterio-coronary disease. in the field of oncology, it has been shown that the growth of solid tumors is entirely dependent upon the constant development of new blood vessels and that it is correlated, for the metastasis of certain cancers, with the increasing size of the primary tumor 35 (J. Folkman, New Engl. Med., 285 (1974), 1182-1185] r> _ 17? rjf-1" I A pharmaceutical treatment (that isi- to' say_j?ne— using an angiogenesis inhibitor) can tnus growth of primary tumors, prevent or \ reduce the.

REPLACEMENT SHEET (RULE 26) 308123 formation of metastasis and prevent the appearance of secondary tumors. Such angiogenesis inhibitors are also useful in the treatment of non-neoplastic diseases mentioned above in which angiogenic activity appears.

Therapeutic needs require the constant development of new angiogenesis-inhibitor compounds for the purpose of obtaining active principles which are not only more active but also more specific and less toxic.

The prior art of the present invention is illustrated in particular by patent US-A-3,631,175 which describes pyrano[3,2-d]oxazole derivatives having fungicidal properties. Compounds with anti-angiogenic activity are known (EP-A-357,061, EP-A-354,787, 15 EP-A-354,767) but have fumagillol type structures.

The present invention relates to new compounds having a tetrahydropyrano[3,2-d]oxazolone structure which are structurally and pharmacologically original when compared with compounds described in the prior 20 art.

More particularly, the subject of the present invention is the compounds of general formula (I): Rl R< X 0==( O R,0 Re k (I) in which: • Rj is chosen from the radical R and the radical -NH-CO-R, • R is chosen from an amino radical and an alkylamino, dialkylamino, alkyl, alkenyl, alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy or heteroaryloxy radical, REPLACEMENT SHEET (RULE 26) 308123 • R2 is chosen from hydrogen and an alkyl radical, • R3 is chosen from hydrogen, an alkyl radical, a hydroxyl radical, an alkoxy radical, an aryl radical, an arylalkyl radical, a radical -(CH2)n-ORB and a radical - (CH2) n-NRaRs, • R« represents hydrogen or else forms a bond with Y, • R5 is chosen from hydrogen, an alkyl radical, an aryl radical, an arylalkyl radical, a heteroaryl radical and a heteroarylalkyl radical or else forms a bond with Y, • Rs is chosen from hydrogen, an alkyl radical an alkyl epoxy radical, an arylalkyl radical, an arylalkyl epoxy radical, an alkenyl radical, ^n alkynyle radical, an alkoxycarbonyl radical, a carboxyl radical, an aryl radical and a heteroaryl radical.

• R, is chosen from hydrogen, an alkyl radical, an arylalkyl radical, a radical -(CH2)n-ORB, a radical - (CH2)n-0-C0-RB and a radical - (CH2) n-NR8R9, • R8 and R,, which may be identical or different, are chosen, independently of each other, from hydrogen, an alkyl radical, an aryl radical and an arylalkyl radical, • n takes a value chosen from 1, 2, 3 and 4, • X and Y are such that: ♦ X is chosen from hydrogen, a hydroxyl radical, an alkoxy radical, an amino radical, an alkyl- amino radical, a dialkylamino radical, a radical -O-CO-R'j and a radical -NH-CO-R'lf where R'j has the same definition as Rx above and Y represents hydrogen, REPLACEMENT SHEET (RULE 26) 3081 - 4 -or a2 tematively, ♦ X represents hydrogen and Y forms a bond with R4 or Rs, or alternatively, ♦ X and Y together form a methylene group, a group =CH-alkyl, a group =CH-aryl or a group =CH-arylalkyl, or alternatively, ♦ X and Y together form an oxo group, 10 or alternatively, ♦ X and Y together form an oxirane ring with the carbon atom which bears them, or alternatively.

♦ X and Y together form a hydroxyimino radical or 15 a radical ^N-O-CO-R'i, where R'T has the same definition as Rj defined above, or alternatively, ♦ X is chosen from an alkyl radical, an arylalkyl 20 radical and a radical «/R» -ch2-sn Rk and Y is chosen from hydrogen, a hydroxyl group 25 and a radical O-CO-NH-CO-R' where R' has the same definition as R defined above, or forms a bond with r4 or rs, • r, and which may be identical or different, are chosen, independently of each other, from an alkyl radical, an aryl radical, an arylalkyl radical, a heteroaryl radical and a heteroarylalkyl radical, or alternatively form, together with the sulfur atom which bears them, an optionally substituted radical 35 chosen from thienyl, 1,3 -dihydrobenzo[c]thien-2-yl, 2,3-dihydrobenzo[b]thien-l-yl, perhydrobenzo[c]thien-2-yl and perhydrothienyl, REPLACEMENT SHEET (RULE 26) 308123 it being understood that: the term "alkyl" included in the alkyl, alkylamino, dialkylamino, arylalkyl, arylalkyl-epoxy, heteroarylalkyl and alkylepoxy radicals denotes a radical whose saturated hydrocarbon chain contains from 1 to 10 carbon atoms, in a straight or branched chain, and is optionally substituted, the term "alkenyl" denotes a radical containing from 2 to 10 carbon atoms in a straight or branched chain, optionally substituted, and containing unsaturation in the form of a double 15 bond, the term "alkynyl" denotes a radical containing from 2 to 10 carbon atoms in a straight or branched chain, optionally substituted, and 20 containing unsaturation in the form of a triple bond, the term "alkoxy" included in the alkoxy and alkoxycarbonyl radicals denotes a radical whose 25 saturated hydrocarbon chain contains from 1 to 10 carbon atoms, in a straight or branched cha_.i, and is optionally substituted, the term "aryl" included in the aryl, arylalkyl, 30 aryloxy and arylalkylepoxy radicals denotes an optionally substituted radical chosen from phenyl and naphthyl, the term "heteroaryl" included in the heteroaryl, 35 heteroaryloxy and heteroarylalkyl radicals denotes an optionally substituted radical chosen from furyl, thienyl, thiazolyl, imidazolyl, REPLACEMENT SHEET (RULE 26) 308123 thiadiazolyl, tetrazolyl, pyridyl, guinolyl, isoquinolyl, indolyl and isoindolyl, and that the terra "optionally substituted" means that the radicals thus qualified may optionally be substituted with one or more chemical moieties chosen from: hydroxy, O-CO-R'j, where R'j has the same definition as Rx defined above, alkoxy, - alkyl, alkenyl, alkynyl, epoxy, alkylthio, halogen, chosen from fluorine, chlorine, bromine and iodine, - trihalomethyl, nitro, amino, alkylamino and dialkylamino, carboxyl, alkoxycarbonyl, alkylcarbonyl, - alkoxycarbonylalkyl, carboxylalkyl, aryl, and heteroaryl, their possible geometric isomers and optical isomers, in pure form or in the form of a mixture, their possible pharmaceutically acceptable addition salts with an acid, and their possible S-oxides, N-oxides or quaternary ammonium salts.

The present invention also covers the process for the preparation of the compounds of formula (I), characterized in that the furyllithium of formula (II) is treated with the compound of formula (III) : REPLACEMENT SHEET (RULE 26) 308123 R-rt-u <H) Y' (IH) "7 o o where R2, R3, Rs, R£ and R7 are as defined above, 5 in a polar, aprotic solvent, for example tetrahydrofuran, at a suitable temperature chosen within a range from -100°C to 30°C, preferably at -78 °C, in order to lead to the furylcarbinol of formula (IV) \ > OH in which R2, R3, R5, R6 and R7 are as defined above, which product, when subjected to oxidation, for example in pyridinium chlorochromate, N-bromosuccinimide or tert-butyl hydroperoxide, in the presence of an acid such as camphorsulfonic acid or meta-chloroperbenzoic acid, in a suitable solvent such as dichloromethane or 20 tetrahydrofuran, at a temperature of between 0°C and 22°C, is rearranged into the pyranone of formula (V) in which R2, R3/ R5, R6 and R7 are as defined above, which pyranone of formula (V) is subjected to the action of 2-chloroacetyl isocyanate in order to obtain the dihydropyrano [3,2-b] oxazole-2-6-dione of formula (Ia) : REPLACEMENT SHEET (RULE 26) 308123 this being a specific case of the compounds of formula 5 (I) where represents the -CH2-C1 radical, X and Y together form an oxo group and R4 represents hydrogen, which compound of formula (Ij may be cleaved, under the action of an alcohol such as methanol, or of a weak 10 base, into a compound of formula (VI): and which is subjected to the reactions presented in 15 reaction schemes I, II and III below: REPLACEMENT SHEET (RULE 26) 30812 Reaction Scheme I- A' m alkyl, arylalkyl Alk m alkyl - —>: when Rs = H The reactions presented in reaction schemes (I), (II), and (III) were thus carried out: Reaction 1: Reduction of the ketone function to 10 alcohol is carried out in a suitable solvent, for example tetrahydrofuran, at low temperature, from -78°C to 20°C, the reducing agent being chosen from the hydrides usually used for this type of reduction. A particularly suitable reducing agent in the present 15 reaction is lithium triethylborohydride.

REPLACEMENT SHEET (RULE 26) 308123 Reaction 2: Etherification of the alcohol function is carried out according to standard methods known to those skilled in the art. For example, the alcohol, treated with a base such as sodium hydride, is 5 subjected to the action of an alkyl halide of formula Alk-X where Alk represents an alkyl chain as defined above and X represents a halogen atom.

Reaction 3 The alcohol function is subjected to 10 dehydration according to standard techniques, for example by heating in the presence of para-toluenesulfonic acid in benzene.

Reaction 4: The hydrogenation reactions are carried 15 out in a conventional manner in the presence of catalytic amounts of palladium, and hydrogen, at atmospheric pressure or under a low pressure, at a temperature of between 10°C and 80°C.

Preferred operating conditions for the catalytic 20 hydrogenations of the present invention are those in which the hydrogen is at atmospheric pressure and at room temperature, the reactions being continued until the compound to be hydrogenated has totally disappeared.

Reaction 5: Esterification of the alcohol function is obtained by the action of a halide of formula R' -CO-X where X represents a halogen and R' is as defined above, on the alkoxide obtained conventionally 30 from the alcohol which it is desired to esterify.

Reaction 6: Reaction performed under the same operating conditions as those used for Reaction 5 described above, replacing the halide R'-CO-X by the 35 isocyanate of formula R'-CO-NCO, where R' is as defined above.

REPLACEMENT SHEET (RULE 26) 30b12i Reaction 7: The ketone function is subjected here to nucleophilic attack under the conditions known to those skilled in the art, for example attack by an alkyllithium or by an arylalkyllithium, in which the 5 terms alkyl and arylalkyl are as defined above.

-Reaction Scheme II- Alk, Alk' ■ alkyl Reaction 8: Conversion of the ketone function into an amine function is obtained by treatment with ammonium acetate (in order to obtain a primary amine), 15 by an amine of formula H2NAlk (in order to obtain a secondary amine) or by an amine of formula HNAlkAlk' (in order to obtain a tertiary amine), where Alk and Alk' each represent an alkyl chain as defined above. The reaction is carried out in the presence of sodium REPLACEMENT SHEET (RULE 26) 3081 ?. cyanoborohydride, in a polar protic solvent, for example an alcoholic solvent, in methanol or ethanol.

Reaction 9: Reaction with hydroxylamine hydrochlo-5 ride and sodium acetate allows the expected oxime to be obtained. The reaction medium is a polar aprotic, preferably alcoholic medium, for example methanol or ethanol. The reaction temperature is chosen, as a function of the solvent used, within a rang*; from 20°C 10 to 80°C, for example at 40°C in methanol.

Reaction 10: The oxime (XIX) is treated as described in Reactions 5 or 6.

Reaction 11: The amine function is treated as described in Reactions 5 or 6.

REPLACEMENT SHEET (RULE 26) 308123 -Reaction Scheme III- A « alkyl, aryl, arylalkyl when Rs = H Reaction 12: The compound of formula (VI) is used in a Wittig reaction under the action of a compound of formula Ph3P=CH2, in order to obtain the compound of 10 formula (XXIV) , or under the action of a compound of formula Ph3P-=CH-A where A represents alkyl, aryl or arylalkyl as defined above. This reaction is carried out in tetrahydrofuran at a temperature of between 60°C and 70°C, the phosphonium ylides being obtained by the 15 action of potassium tert-butoxide.

REPLACEMENT SHEET (RULE 26) 14 308123 Reaction 13a: The spiro-epoxy function is obtained by the action of dimethyl sulfide ylide on the compound of Example (VI) .

Reaction 13b: The spiro-epoxy function is obtained by dichloromethane, at 0°C.

Reaction 14: Attack of the epoxide is carried out by 10 a compound of formula RaSNa where Ra is as defined dimethylformamide. A second attack is then carried out by a halide of formula Rb_X where Rb is as defined above and X represents a halogen atom, this attack being 15 carried out in the presence of silver bromide in trichloromethane. In the case where Ra and Rb together form a ring, the reaction will be carried out in a single step using a compound of formula the set of compounds of formula (VI) to (XXIX) forming the compound of formula (Id) which is finally subjected 20 to the action of a halide of formula R-CO-X, where R is as defined above and X represents a halogen atom, under the operating conditions described for reaction 5 define'3 above, or alternatively, subjected to the action of an isocyanate of formula R-CO-NCO, where R is 25 as defined above, under the operating conditions described for reaction 6. defined above. These reactions are expressed by the following scheme: the action of meta-chloroperbenzoic acid in above, in a suitable solvent, for example REPLACEMENT SHEET (RULE 26) 308123 where R, R2, R3( R4, R5, Rs, R7 X and Y are as defined above, the set of compounds of formula (Ib) and (Ic) forming 5 the set of compounds of formula (I) which are purified, where appropriate, by a standard purification technique, whose geometric isomers and optical isomers are separated, if desired, by a standard separation technique, and which are converted, where appropriate, 10 into their N-oxides, S-oxides, their pharmaceutically acceptable addition salts with an acid or into their quaternary ammonium salts.

The compounds of the present invention may also be prepared from a compound of formula (II'): o where R2/ R3, R5 and R, are as defined above, on which compound a lithium reagent of formula (III') R6-Li (III') in which Rfi is as defined above, is reacted under the operating conditions described for the reaction of the compound of the formula (II) with the compound of formula (III), in order to obtain the compound of formula (IV) defined above.

The compounds of formula (I) for which Rs 30 represents an alkyl, alkenyl, alkynyl or alkylepoxy radical may advantageously be obtained according to the following synthetic scheme: REPLACEMENT SHEET (RULE ?">) 308123 X—/1 I) oxidative rearrangement ii) Cl-CH2-CO- NCO iii) cleavage where R2, R3, R5 and R7 are as defined above and R'6 represents an alkyl radical or an arylalkyl radical, 5 the alkyl chain containing from 1 to 8 cai-bon atoms.

The radicals -CO-NH-CO-R and -CO-NH-CO-R', where R and R' are as defined above, when they substitute the compounds of formula (I) may advantageously be selectively cleaved into radicals -CO-NH2. This cleavage 10 reaction is preferably carried out on a column of silica, by liquid chromatography (HPLC), for example on an RP18 column, or under controlled acidic or basic conditions.

In general, the separations of any geometric or 15 optical isomers of the compounds obtained in each of the steps of the syntheses described above may be carried out at any moment considered to be suitable by those skilled in the art. Similarly, depending on the degree of stability of the substituents borne by the 20 compounds, the various reactions presented above may be carried out in an order different from that presented in the present invention and considered to be more suitable by those skilled in the art.

The compounds of formula (I) have advantageous 25 pharmacological properties since these compounds are REPLACEMENT SHEET (RULE 26) A 308123 powerful angiogenesis inhibitors which have the advantage of being generally much less toxic than the reference compounds. They thus have an excellent therapeutic index. These compounds also find a 5 therapeutic application as antitumor agents, in inhibition of the formation and growth of metastases, as well as in the treatment of diabetic retinopathy, rheumatoid arthritis, hemangiomas and arterio-coronary diseases, and more generally in complaints due to or 10 associated with angiogenesis disorders.

The subject of the present invention is also pharmaceutical compositions containing the compounds of formula (I) , their possible optical and/or geometric isomers and their possible pharmaceutically acceptable 15 addition salts with an acid, alone or in combination with one or more inert and non-toxic vehicles or excipients.

Among the pharmaceutical compositions according to the invention, mention will be made more 20 particularly of those which are suitable for oral, parenteral, nasal, rectal, perlingual, transdermal, ocular or respiratory administration, and in particular simple or sugar-coated tablets, sublingual tablets, gelatin capsules, suppositories, creams, ointments, 25 dermal gels, patches, injectable or drinkable preparations, aerosols, eyedrops or nose drops. The appropriate dosage varies depending on the age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated 30 treatments, and ranges between 0.01 and 1 g per day, in one or more administrations.

The examples which follow illustrate the invention but do not limit it in any way. The starting materials are known or are prepared from known 35 procedures.

REPLACEMENT SHEET (RULE 26) 308 1 2 EXAMPLE 1: l-Chloroacetyl-5-(hept-l-ynyl)-5-methyl- dihydropyrano[3,2-d]oxazole-2,6-dione Step A: 8-(2-furyl)non-6-yl-8-ol 46.95 ml of n-butyllithium (2.5M) in hexane are added dropwise to a solution containing 14 ml (106.7 mmol) of 1-heptyne in 150 ml of diethyl ether cooled to -78°C and under a nitrogen atmosphere. 10 Stirring is continued for one hour at -78°C. 12.89 ml (106.7 mmol) of 2-acetylfuran in 150 rr.l of toluene are then added. The mixture is stirred for a further one hour at -78 °C. The solution is then hydrolyzed by saturated aqueous sodium chloride solution and then 15 extracted with pentane. The organic phases collected are dried over magnesium sulfate and then filtered and concentrated. 22 g of a brown liquid, corresponding to the expected product, are obtained and used in their present state in the subsequent synthesis.

Step B: 2-(heptyn-l-yl)-2-methyl-3-oxo-dihydro-[2H] pyran-6-ol 8.62 g of (48.4 mmol) of N-bromosuccinimide are added to a solution containing 10 g (48.4 mmol) of the 25 compound obtained in the above step in 750 ml of a tetrahydrofuran/water mixture (2:1) cooled to 0°C. The mixture is stirred for one hour at 0°C. The reaction medium is then neutralized by saturated aqueous sodium hydrogen carbonate solution and then extracted with 3 0 pentane. The usual treatment of the organic phaoes gives 11.63 g of an orange/brown liquid, corresponding to the expected product, which is used in its present state in the subsequent synthesis.

Step C: 1-chloroacetyl-5-(hept-l-ynyl)-5-methyl- dihydropyrano[3,2-d]oxazole-2,6-dione .75 g (7.6 ml; 90 mmol) of chloroacetyl isocyanate are added to 10 g (45 mmol) of the compound REPLACEMENT SHEET (RULE 26) 30812 obtained in the above step, in dichloromethane, under an inert atmosphere and at 0°C. The reaction medium is stirred until the starting material has disappeared (reaction monitored by thin layer chromatography). The 5 solution is then hydrolyzed by saturated aqueous sodium chloride solution and then extracted with dichloro-methane. The usual treatment of the organic phase gives, after purification by chromatography on a column of silica (eluent: 4/1 heptane/ethyl acetate), 4 g of the expected compound along with 2.8 g of the two diastereoisomers A and B of 5-(hept-l-yn-l-yl)-5-methyldihydropyrano[3,2-d]oxazole-2,6-dione, in the form of a brown oil which crystallizes (Rf = 0.28, diastereoisomer A; Rf = 0.16, diastereoisomer B; eluent: 2/1 diethyl ether/dichloromethane).

Elemental analysis: (empirical formula: C16H20ClNO5 molecular mass: 341.79) C H N CI % found 56.30 5.93 4.06 10.63 % calculated 56.23 5.90 4.10 10.37 EXAMPLE 2: l-Chloroacetyl-5-(hept-l-enyl)-5-methyl- dihydropyrano[3,2-d] oxazole-2,6-dione 2 g (115.9 mmol) of the compound obtained in Example 1 are dissolved in 100 ml of benzene in the presence of 1 g of Lindlar catalyst. The mixture is stirred in the presence of hydrogen at atmospheric pressure until the starting material has completely disappeared. After filtration through Celite and concentration of the filtrate under reduced pressure, 2 g of a white solid are obtained.

REPLACEMENT SHEET (RULE 26) 308123 Elemental analysis: (empirical formula: C16H22C1N0S molecular mass: 343.81) C H N CI % found 56.16 6.51 3.88 11.10 % calculated 55.90 6.45 4.0"7 10.31 EXAMPLE 3: l-Chloroacefcyl-5-(3-pentyloxiran-2-yl)- -methyldihydropyrano [3,2-d] oxazole-2, 6-dione 60 mg (0,18 mmol) of the compound obtained in Example 2 are subjected to an oxidation reaction in the presence of 6 ml of a solution of acetone saturated with dimethyldioxirane at 0°C. The reaction medium is stirred for one hour at this temperature. The solvent 15 is evaporated off under reduced pressure and the oily residue thus obtained is distilled azeotropically with toluene. After concentration under reduced pressure and drying under vacuum, the expected compound is obtained in the form of a lyophilizate.

Elemental analysis: (empirical formula: C16H22C1N06 molecular mass: 359.81) C H N CI % found 53.4 9 6.19 3.74 9.77 % calculated 53.41 6.16 3.89 9.85 EXAMPLE 4; 6-[(l-Chloroacetyl-5-(3-pentyloxiran-2- yl)-5-methyltetrahydropyrano[3,2-d]-oxazol-2-one]spiro-2'-oxirane (Isomer o£ the compound of Example 13) REPLACEMENT SHEET (RULE 26) 3o r123 Step A: 5' hept-l-ynyl)-5-methyl-6-methylene-dihydropyrano[3,2-d]oxazol-2-one 28 ml of a solution of potassium tert-butoxide (1M) in 5 tetrahydrofuran are added to 10 g (28 mmol) of triphenylmethylphosphonium bromide suspended in 40 ml of tetrahydrofuran. The reaction medium is heated for one hour at 60-70°C. The mixure is then cooled to 0°C and 2.5 g (9.35 mmol) of diastereoisomer A of 5-(hept-10 1-ynyl) -5-methyl-dihydropyrano [3, 2-d] oxazole-2, 6-dione, obtained in Example 1, diluted in 30 ml of tetrahydrofuran are added. After stirring for two hours at room temperature, the reaction medium is hydrolyzed by saturated sodium chloride solution and then 15 extracted with ether. The usual treatment of the organic phase gives, after purification by chromatography on silica gel (eluent: 2/1 heptane/ethyl acetate), 2.08 g of the expected compound.

Step B: 6-[5-(hept-l-ynyl)-5-methyltetrahydro pyrano [3,2-d]oxazol-2-one] spiro-2'-oxirane g (20.5 mmol) of 70% meta-chloroperbenzoic acid are 25 added to a solution of 1.8 g (6.8 mmol) of the compound obtained in the above step, in 23 0 ml of dichloromethane at 0°C. After returning to room temperature, the reaction medium is stirred for 12 hours. -The solid form is filtered off and the filtrate 30 is washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated aqueous sodium chloride solution. The usual treatment of the organic phase gives 5 g of a white solid which, when purified by chromatography on silica gel (eluent: 1/1 35 heptane/ethyl acetate), lead to 1.6 g of the expected compound.

REPLACEMENT SHEET (RULE 26) D 308123 Step C: 6-[5-(hept-l-enyl)-5-methyltetrahydro-pyrano[3,2-d]oxazol-2-one]spiro-2'-oxirane 670 mg (2.39 mmol) [lacuna] are used in the hydrogenation reaction described in Example 2 in order to give 660 mg of a white solid.

Step D: 6-[5-(3-pentyloxiran-2-yl)-5-methyl-10 tetrahydropyrano[3,2-d]oxazol-2- one]spiro-2'-oxirane 660 mg (2.35 mmol) of the compound obtained in the above step are oxidized under the conditions described 15 in Example 3 to give 650 mg of the expected compound in the form of a white powder.

Step E: 6- [l-chloroacetyl-5-(3-pentyloxiran-2-yl)-5-methyltetrahydropyrano-20 [3,2-d]oxazol-2-one]spiro-2'-oxirane 467 fil (0.746 mmol) of n-butyl lithium are added to 200 mg (0.7.\ mmol) of the compound obtained in the above step, in 5 ml of tetrahydrofuran at -78°C. After 25 stirring for half an hour, 84 mg (0.746 mmol) of 2-chloroacetyl chloride are added. After stirring for 10 minutes, the reaction medium is hydrolyzed by saturated sodium chloride solution and then extracted with diethyl ether. The usual treatment of the organic phase 30 gives 140 mg of a white solid corresponding to th» expected product.

Rf = 0.39 (1/1 heptane/ethyl acetate).

REPLACEMENT SHEET (RULE 26) Elemental analysis 308123 (empirical formula: C17H2<ClNOe molecular mass: 373.84) % found % calculated c 54 .23 54.62 h 6 .48 6.47 n 3 .59 3 .75 EXAMPLE 5: 6-[l-Chloroacetylcarbamoyl-5-(3- pentyloxiran- 2 -yl) - 5 -methyltetrahydropyrano [3,2-d] oxazol-2-one] spiro-2' -oxirane Compound obtained starting from 2-acetylfuran and 1-heptyne according to the procedure described in Example 4, replacing in step E the 2-chloroacetyl chloride by 2-chloroacetyl isocyanate.

Elemental analysis: (empirical formula: C^sClNA molecular mass: 414.85) % found % calculated c 51.41 51. 86 H 6.02 6.04 n 6.56 6.72 Working according to the procedure described in Example 4, the compounds of Examples 6 and 7 are obtained using the appropriate acyl chloride.

EXAMPLE 6: 6- [l-Cinnamoyl-5- (3-pentyloxiran-2-yl) -5-methyltetrahydropyrano [3,2 -d] oxazol-2-one] spiro-2' - oxirane (diastereoisomer A) Rf = 0.34 (1/1 heptane/ethyl acetate) REPLACEMENT SHEET (RULE 26) £< _24_ 30 8 1 23 Elemental analysis: (empirical formula: C24H29N06 molecular mass: 427.50) C H N % found 66.84 6.89 3.13 % calculated 67.43 6.84 3.28 EXAMPLE 7: 6-[l-Cinnamoyl-5-(3-pentyloxiran-2-yl)- -methyltetrahydropyrano[3,2 - d]oxazol-2-one] spiro-2'-oxirane (diastereoisomer B) Rf = 0.4 (1/1 heptane/ethyl acetate) Elemental analysis: % found % calculated C 66.85 67.43 (empirical formula: C24H29N06 molecular mass: 427.50) H 6 . 80 6.84 N 3 .29 3 .28 The compounds of Examples 8 and 9 are obtained according to the procedure described in Example 4, using an excess of 2-chloroacetyl chloride in step E 20 and using the appropriate alkyne in step A.

EXAMPLE 8s 6-[l-Chloroacetyl-5-(1-hydroxy-2-chloro- heptyl)-5-methyltetrahydro-pyrano[3,2-25 d]oxazol-2-one]spiro-2'-oxirane Elemental analysis: (empirical formula: C17H25C12N06 molecular mass: 410.30) REPLACEMENT SHEET (RULE 26) 308123 C H N CI % found 49.69 6.13 3.29 17.65 % calculated 49.77 6.14 3.41 17.28 EXAMPLE 9; 6- [l-Chloroacetyl-5- (l-hyd.roxy-2-chloro- 5-pentylphenyl) -5-methyl-tetrahydro pyrano [3,2-d]oxazol-2-one]spiro-2° -oxirane Elemental analysis: (empirical formula: C21H25Cl2NOs molecular mass: 458.34) C H N CI % found 54.45 5.62 2.70 17.08 % calculated 54.17 5.46 3.01 16.75 EXAMPLE 10 : 6- [l-Chloroacetyl-5-heptyl-5-methyl-15 tetrahydropyrano [3,2-d] oxazol-2- one]spiro-2'-oxirane Compound obtained according to the procedure described in Example 4, steps A, B and E, starting from 5-methyl-20 5-heptyldihydropyrano [3,2-d] oxazole-2, 6-dione in step A, which is itself obtained by catalytic hydrogenation (palladium, barium sulfate, in ethyl acetate, 1 atmosphere) of the diastereoisomer A of 5-(hept-l-ynyl) -5-methyldihydropyrano [3,2-d] oxazole-2, 6-dione 25 obtained in Example 1.

Elemental analysis: (empirical formula C17H2eClN05 molecular mass: 3 59.85) C H N CI % found 56.62 7.20 3.78 10.51 % calculated 56.74 7.28 3.89 9.85 REPLACEMENT SHEET (RULE 26) 308123 EXAMPLE 11-1: l-Chloroacetyl-5-hepty1-dihydro-pyrano[3,2-d]oxazole-2,6-dione (Isomer of Example 11-2) g (24.5 mmol) of the compound obtained according to the procedure described in step A of Example 1 starting from furaldehyde and 1-heptyne, are placed in contact with 1.5 g of Lindlar catalyst in 100 ml of benzene, under a hydrogen atomosphere. 5 g of l-(furan-2'-yl)octan-l-ol are obtained and are treated according to the procedures described in steps B and C of Example 1. The crude product is isolated by chromatography to give the title compound along with the compound of Example 11-2.

Rf = 0.39 (60/40 cyclohexane/ethyl acetate) Elemental analysis: (empirical formula: C15H22C1N05 molecular mass: 331.79) C H N CI % found 54.30 6.20 4.24 10.68 % calculated 54.30 6.68 4.22 10.68 EXAMPLE 11-2: 1-Chloroacetyl-5-heptyldihydropyrano- [3,2-d]oxazole-2,6-dione (Isomer of Example 11-1) Compound obtained during the purification of the crude product obtained in Example 11-1.

R£ = 0.28 (60/40 cyclohexane/ethyl acetate) Spectral characteristics: 1H NMR, (DMSO) , 8 (ppm) : 6(lH,d); 4.82 (lH,d); 4.75 (lH,m); 4.72 (lH,d); 4.17 (lH,dd); 3.0-2.8 (2H,AB); 1.72 (lH,m); 1.52 (lH,m); 1.45-1.15 (10H,m); 0.82 (3H,t).

REPLACEMENT SHEET (RULE 26) 308123 27 - EXAMPLE 12: l-Chloroacetyl-5-[3-(3-phenylpropyl)- oxiran-2-yl]-5-methyldihydropyrano-[3,2-d]oxazole-2,6-dione Compound obtained according to the procedure described in Examples 2 and then 3, using, in step A of Example 1, the appropriate acetylenic derivative.

Elemental analysis: (empirical formula: C20H22ClNO6 molecular mass: 407.85) C H N CI % found 59.23 5.38 3.25 8.79 % calculated 58.90 5.44 3.43 8.69 EXAMPLE 13: 6-[l-Chloroacetyl-5-(3-pentyloxiran- 2-yl) -5-methyltetrahydropyrano- [3,2-d] -oxazol-2 -one] spiro -2' -oxirane (Isomer of the compound of Example 4) Step A: 5-(hept-l-enyl)-5-methyl-dihydropyrano-[3,2-d]oxazole-2,6-dione The diastereoisomer A of 5-(hept-l-yn-l-yl)-5-methyldihydropyrano[3,2-d]oxazole-2,6-dione obtained in step C of Example 1, is subjected to catalytic hydrogenation according to the procedure described in Example 2.

Step B: 6-[l-chloroacetyl-5-(3-pentyloxiran- 2-yl)-5-methyltetrahydropyrano[3,2-d] -oxazol-2-one]spiro-2'-oxirane 1.25 g (4.7 mmol) of the compound obtained in the above s'_ep, in 15 ml of tetrahydrofuran, are reacted at 0°C with dimethyl sulfide ylide, obtained from 4.92 g REPLACEMENT SHEET (RULE 26) 3ifi123 (24.1 mmol) of trimethylsulfonium iodide and 24.1 mmol of n-butyllithium in 15 ml of tetrahydrofuran. The reaction medium is stirred for 15 hours, from 0°C to room temperature, and then hydrolyzed by saturated £ aqueous sodium chloride solution and extracted with diethyl ether. The usual treatment of the organic phase gives 1.3 g of a yellow solid which is purified by chromatography on silica gel. This compound is then subjected to the reactions described in steps D and E 10 of Example 4.

Rf = 0.35 (1/1 heptane/ethyl acetate) Elemental analysis: (empirical formula: C17H24C1N0S molecular mass: 373.84) C H N CI % found 54.38 6.38 3.58 9.60 % calculated 54.62 6.47 3.75 9.ft8 EXAMPLE 14: 1-Carbamoyl-5-(3-pentyloxiran-2-yl)-5-methyldihydropyrano[3,2-d]oxazole-2,6-dione The diastereoisomer A of 5- (hept-l-yi.yl) -5-methyldihydropyrano [3,2-d] oxazole-2, 6-dione, obtained in step C of Example 1, is subjected to catalytic hydrogenation, epoxidation, according to the procedures described in Examples 2 .and 3, and then acylation by 2-chloroacetyl isocyanate, according to the procedure described in Example 5, followed by a passage through silica.

Spectral characteristics: *H NMR, (DMSO), 5 (ppm): 7.7 (lH,s); 7.3 (lH,s); 6.2 (1H,d) ; 4.95 (lH,ra); 3.0 (4H,m) ; 1.8 (2H,m) ; 1.6-1.3 (9H,m); 0.9 (3H,t) REPLACEMENT SHEET (RULE 26) 308123 29 EXAMPLE 15: l-Chloroacetyl-5-(hept-l-enyl)- 6 -hydroxy- 5-methyl tetrahydropyr ano-[3,2-d]oxazol-2-one Step A: 5-(heptyn-l-yl)-6-hydroxy-5-methyl-tetrahydropyrano[3,2-d]oxazcl-2-one 210 mg (0.786 mmol) of the diastereoisomer A obtained 10 in Example 1 are treated with 1.57 mmol of Super-Hydride (LiEt3BH) in tetrahydrofuran at -78°C. After stirring for 15 minutes, the reaction medium is hydrolyzed successively with water, aqueous 10% sodium hydroxide solution and then aqueous 15% hydrogen 15 peroxide solution and then extracted with ethyl ether. After drying the organic phase over sodium sulfate and then concentration under vacuum, 200 mg of the expected product are obtained in the form of a yellow oil.

Step B-. l-chloroacetyl-5-(hept-l-enyl)- The compound obtained in the above step is subjected to catalytic hydrogenation according to the procedure described in Example 2 and is then acylated using 2-chloroacetyl chloride according to the procedure 3 0 Spectral characteristics: *H NMR, (DMSO), 8 (ppm): 5.7 (lH,d); 5.5 (2H,m); 5.35(1H,d); 4.85 (2H,dd); 4.45 (lH,m); 3.6 (lH,m); 2.4-2.2 (3H,m); 2.0 (lH,m); 1.5-1.3 (9H,m); 0.9 (3H,t) 6 - hydroxy - 5 - me t hy 11 e t r ahy dr opyr ano -[3,2-d]oxazol-2-one described in step E of Example 4.

REPLACEMENT SHEET (RULE 26) 308123 EXAMPLE 16: l-Chloroacetylcarbamoyl-5-(hept-l-ynyl)- 6-hydroxy-5-methyltetrahydropyrano-[3,2-d]oxazol-2-one Compound obtained starting from the diastereoisomer A obtained in Example 1 treated with Supei-Hydride (LiEt3BH) according to the operating conditions of step A of Example 15, and then with chloroacetyl isocyanate according to the procedure described in step E of Example 4.

Spectral characteristics: *H NMR, (DMSO) , 8 (ppm) : 6.0 (lH,d); 5.45 (lH,d); 4.6 (2H,s); 4.55 (lH,m); 3.8 (lH,m) ; 2.4 (2H,m) ; 2.3-2.15 (4H,m); 1.5-1.25 (6H,m) ; 0.9 (3H,t).

EXAMPLE 17: 1-Chloroacetylcarbrmoyl-6-chloroacetyl- carbamoyloxy-5-(hept-l-ynyl)-5-methyltetrahydropyrano [3,2-d]oxazol-2-one Compound obtained according to the procedure of Example 16, using an excess of chloroacetyl isocyanate in the final step.

Elemental analysis: (empirical formula: C20H25Cl2N3OB molecular mass: 506.34) C B.N CI % found 47.09 5.01 8.22 14.23 % calculated 47.44 4.98 8.30 14.00 REPLACEMENT SHEET (RULE 26) at 308123 EXAMPLE 18: 6- [l-Benzoyl-5- (3-pentyloxiran-2-yl) -5-methyltetrahydropyremo[3,2-d]oxazol-2-orb]spiro-2'-oxirane Compound obtained according to the procedure described in Example 4, replacing, in step E, the 2-chloroacetyl chloride by benzoyl chloride.

Spectral characteristics: *H NMR, (DMSO), 8 (ppm): 7.6-7.4 (5H,m); 6.1 (lH,d); 4.8 (1H,q); 3.1 (1H,d); 2.85 (2H,m); 2.7 (lH,d); 2.3 (2H,m); 1.8 (2H,m); 1.6-1.4 (9H,m); 0.9 (3H,t).

Working according to the procedures described in 15 Examples 1 and 2, starting with 5-phenylpentyne, the compounds of Examples 19 and 20 are respectively obtained: EXAMPLE 19: l-Chloroacetyl-5-methyl-5-(5-phenylpent- 1-ynyl)dihydropyrano[3,2-d]oxazole-2,6-dione Elemental analysis: (empirical formula: C20H20ClNO5 molecular mass: 389.84) C H N CI % found 61.44 5.17 3.53 9.53 % calculated 61.62 5.17 3.59 9.09 EXAMPLE 20: l-Chloroacetyl-5-methyl-5- (5-phenylpent-30 1-enyl)dihydropyrano[ 3 , 2 - d]oxazole-2,6- dione REPLACEMENT SHEET (RULE 26) 308123 Spectral characteristics: :H NMR, (DMSO) , 5 (ppm) : 7.5-7.3 (m,5H); 6.0 (d,lH); 5.65 (m, 1H) ; 5.35 (broad d, 1H) ; 4.97-4.7 (m,3H); 3.0 (m,2H); 2.6 (broad triplet, 2H); 2.3 (m,2H); 1.6 5 (m,2H); 1.4 (s,3H). example 21t 1-Chloroacetyl-5-methyl-5-(5-phenyl-pentyl) dihydropyrano [3, 2-d] oxazole-10 2,6-dione Compound obtained by catalytic hydrogenation of the compound obtained in Example 19.

Elemental analysis: (empirical formula: C20H24ClNO5 molecular mass: 3 93.87) C H N CI % found 60.88 6.29 3.45 9.04 % calculated 60.99 6.14 6.56 9.00 EXAMPLE 22: 1-Chloroacetyl-5-heptyl-5-methyl-dihydropyrano-[3,2-d]oxazole-2,6-dione Compound obtained by catalytic hydrogenation of the compound obtained in Example 1.

Elemental analysis: (empirical formula: C16H24C1N05 molecular mass: 345.83) % found % calculated C 55.92 55.57 H 7.03 7.00 N 3 .85 4.05 CI .16 10.25 REPLACEMENT SHEET (RULE 26) 30R123 EXAMPLE 23: l-Chloroacetyl-5-(3-methyloxyprop- 1-ynyl)-5-methyldihydropyrano[3,2-d] -oxazole-2,6-dione Compound obtained according to the procedure described for Example l, starting from 3-methoxypropyne.

Elemental analysis; (empirical formula: C13H14C1N06 molecular mass: 315.71) C H N CI % found 48.89 4.51 4.17 11.42 % calculated 49.46 4.47 4.44 11.23 EXAMPLE 24: 1-Chloroacetyl-5-(5-methylhex-l-ynyl)-5-methyldihydropyrano[3,2-d]oxazole-2,6• dione Compound obtained according to the procedure described for Example 1, starting from 5-methylhexyne.

Elemental analysis: (empirical formula: C16H20ClNO5 molecular mass: 341.79) % found % calculated C 56.86 56.23 H .81 5.90 N 4.13 4.10 CI .50 10 .37 EXAMPLE 25: l-Chloroacetyl-5- (3-methoxypropyl) - -methyldihydropyrano[3 f 2-d]oxazole-2,6-dione Compound obtained by catalytic hydrogenation of the 30 compound of Example 23.

REPLACEMENT SHEET (RULE 26) Elemental analysis: (empirical formula: C13H18C1N06 molecular mass: 319.74) C H N CI % found 49.08 5.66 4.31 11.27 % calculated 48.83 5.67 4.38 11.09 308123 EXAMPLE 26 : l-Chloroacetyl-5 - (5-metnylhexyl) - -methyldihydropyrano [ 3,2 - d] oxazole - 2,6-dione Compound obtained by catalytic hydrogenation of the compound of Example 24.

Elemental analysis: (empirical formula: C16H24C1N0S molecular mass: 345.83) C H N CI % found 55.85 7.16 3.70 10.00 % calculated 55.57 7.00 4.05 10.25 The Examples 27 and 28 [sic] are obtained from the compound obtained in step B of Example 4, replacing the 2 0 2-chloroacetyl chloride by 2-chloroacetyl isocyanate, according to the procedure described in step E of Example 4.

EXAMPLE 27: 6-[l-Chloroacetylcarbamoyl-5-(hept- l-ynyl) -5-methy1tetrahydropyrano-[ 3,2-d]oxazol-2-one] spiro-2'-oxirane REPLACEMENT SHEET (RULE 26) £> Elemental analysis: 308123 (empirical formula: C1BH23C1N206 molecular mass: 398.85) % found % calculated C 54 .73 54 .21 H .85 5.81 N 7.01 7.02 CI 8.84 8.89 EXAMPLE 28; 6-[1-Carbamoyl-5-(hept-l-ynyl)-5-methyltetrahydropyrano- [3,2-d] oxazol-2■ one] spiro-2' -oxlrants Elemental analysis: (empirical formula: C16H22N205 molecular mass: 322.36) % found % calculated C 59.65 59.62 H 6.94 6.88 N 8.58 JJ.69 EXAMPLE 29: 6-[l-Chloroacetyl-5-[3-(3-phenyl- propyl)oxiran-2-yl]-5-methyltetrahydro-pyrano [ 3,2 - d] oxazol - 2 - one ] spiro -2' -oxirane Compound obtained according to the procedure described in Example 4, steps A to E, using, in step A, the appropriate acetylenic derivative.

Elemental analysis: (empirical formula: C21H24ClNGe molecular mass: 421.88) C H N CI % found 59.67 5.66 3.29 8.91 % calculated 59.79 5.73 3.32 8.40 REPLACEMENT SHEET (RULE 26) 36 - 308123 EXAMPLE 30: 6-[l-Chloroacetyl-5-(1-chloroacetyl- carbaxnoyloxy- 2 - chloro- 5 -phenylpentj 1) -5-methyltetrahydropyrano[3,2-d]oxazol-5 2-one]spiro-2'-oxirane Compound obtained from the compound of Example 9, by treatment with one equivalent of 2-chloroacetyl isocyanate in dichloromethane.

After stirring for 2 hours at 0°C and hydrolysis, the organic puase is extracted with dichloromethane. After drying the organic phase over magnesium sulfate, concentration and trituration in ether, the desired compound is obtained in the form of a white powder.

Elemental analysis: (empirical formula: C24H27C13N20B molecular mass: 577.85) C H N CI % found 49.27 4.67 4.79 18.49 % calculated 49.89 4.71 4.85 18.41 EXAMPLE 31: 1 - Chloroacetylcarbamoyl - 6 - chloroacetyl - carbaxnoyloxy- 5 -hep tyl - 5 -me thyl tetrahydropyrano [3,2 -d] oxazol - 2 -one Compound obtained according to the procedure described for Example 17, starting from the diastereoisomer A obtained in Example 1 (step C) which has been reduced beforehand to 5-methyl-5-heptyldihydropyrano[3,2-d]-oxazole-2,6-dione by catalytic hydrogenation.

Elemental analysis: (empirical formula: C20H29Cl2N3O8 molecular mass: 510.38) REPLACEMENT SHEET (RULE 26) % found % calculated C 46.83 47 .07 - 37 H .70 5.73 N 7.92 8.23 3081 CI 14 .00 13 .89 EXAMPLE 32-1: 1 -Chloroacetylcarbamoyl - 6 - carbamoyloxy-5-heptyl-5-methyltetrahydropyrano-[3,2-d]-oxazol-2-one Compound obtained during the purification by liquid chromatography Example 31.

(HPLC) on RP18 of the compound of Elemental analysis: (empirical formula: C1BH28C1N307 molecular masst 433.89) '% found % calculated C H 49.76 6.50 49.83 6.50 N CI 9.62 8.77 9.68 8.17 The compounds of Examples 32-2, 32-3 and 32-4 below are obtained by successive cleavages by liquid chromatography (HPLC) on an RP18 column, of the compound of Example 17.

EXAMPLE 32-2 : 1 - Chloroacetylcarbamoyl - 6 - carbamoyloxy - (hept-l-ynyl) -5-methyltetrahydropyrano [3,2-d]oxa-ol-2-one Elemental analysis: C % found 50.66 % calculated 50.30 (empirical formula: C1BH24ClN30j molecular mass: 429.86) H N CI .70 9.63 8.10 .63 9.78 8.25 REPLACEMENT SHEET (RULE 26) 308123 EXAMPLE 32-3: 1-Carbamoyl-6-chloroacetylcarbamoyloxy- -(hept-l-ynyl)-5-methyltetrahydropyrano [3,2-d]oxazol-2-one Elemental analysis: (empirical formula: C18H24C1N308 molecular mass: 429.86) C H N CI % found 50.26 5.68 9.43 8.17 % calculated 50.30 5.63 9.78 8.25 EXAMPLE 32-4: 1-Carbamoyl-6-carbamoyloxy-5-(hept-l- ynyl) -5-aethyltetrahydropyrano-[3,2-d]oxazol-2-one Spectral characteristics: *H NMR, (DMSO) , 8 (ppm) : 7.52 (lH,s); 7.11 (lH,s); 6.5 (2H,s); 5.81 (lH,d); 4.6 (lH,t); 4.31 (lH,m); 2.66-2.3 (2H,m) ; 2.25 (2H,t); 1.55-1.25 (6H,m); 1.35 (3H,s); 0.88 (3H,t).

The compounds of Examples 33 and 34 are obtained according to the procedure described in Example 31, using, in step A of Example 1, the appropriate acetylenic derivative.

EXAMPLE 33: 1-Chloroacetylcarbamoyl-6-chloro- acetylcarbamoyloxy-5-(5-phenylpent-1-ynyl)-5-methyltetrahydropyrano-[3,2-d]oxazol-2-one Elemental analysis: (empirical formula: C24H2SC12N308 molecular mass: 554.3 9) REPLACEMENT SHEET (RULE 26) § -39. 30 8 1 2 3 C H N CI % found 51.79 4.45 7.24 13.09 % calculated 52.00 4.55 7.58 12.79 EXAMPLE 34: 1 -Chloroacetylcarbamoyl - 6 - chloroacetyl -5 carbamoyloxy-5-(5-phenylpentyl)-5- methyl-tetrahydropyrano[3,2-d]oxazol- 2 -one Elemental analysis: (empirical formula: C24H29C12N3Ob molecular mass: 558.42) C H N CI % found 51.86 5.19 7.47 12.99 % calculated 51.62 5.23 7.52 12.70 EXAMPLE 35: 1-Chloroacetylcarbamoyl-5-(hept-l-ynyl)-15 5-methyldihydropyrano[3,2-d]oxazole-2,6- dione Compound obtained from the diastereoisomer A (5-(hept- 1-ynyl) -5-methyldihydropyrano[3,2-d]oxazole-2,6-dione) 20 of step C of Example 1, which is reacted with 2-chloroacetyl isocyanate instead of 2-chloroacetyl chloride according to the procedure described in step E of Example 4.

Elemental analysis: (empirical formula: C17H21C1N206 molecular mass: 384.82) C H N CI % found 52.87 5.56 7.16 9.47 % calculated 53.06 5.50 7.28 9.21 t REPLACEMENT SHEET (RULE 26) » 30 8 1 23 EXAMPLE 36: l-Chloroacetylcarbamoyl-5-(5-methylhex- 1-ynyl)-5-methyldihydropyrano[3,2-d]-oxazole-2,6-dione Compound obtained according to the procedure described for Example 35, using the appropriate acetylenic derivative in step A of Example 1.

Elemental analysis: (empirical formula: C17H21C1N20S molecular mass: 384.82) C H N CI % found 53.13 5.59 7.08 9.32 % calculated 53.06 5.50 7.28 9.21 EXAMPLE 37; 1 - Chloroace tylcarbamoyl- 5 - (5 -me thylhex-1-yl)-5-methyldihydropyrano[3,2-d]-oxazole-2,6-dione Compound obtained by catalytic hydrogenation of the compound of Example 35.

Elemental analysis: (empirical formula: C17H25C1N206 molecular mass: 388.85) % found % calculated C 53.03 52.51 H 6.57 6.48 N 7.12 7.20 CI 9.29 9.12 EXAMPLE 38; 1-Carbamoyl-5-(5-methylhexyl)-5- methyldihydropyrano[3,2-d]oxazole-2,6- dione Compound obtained during the purification of the compound of Example 37, by HPLC on RP18.

REPLACEMENT SHEET (RULE 26) Elemental analysis: (empirical formula: C15H24N205 molecular mass: 312.37) 308123 % found. % calculated C 58.10 57.68 H 7. 84 7.74 N 8 . 86 8..97 EXAMPLE 39: 1-Chloroace tyl c arbamoy1 - 5 - hep ty 1 -• -methyldihydropyrano [3,2-d] cxsizole-2, 5-dione Compound obtained according to the procedure of Example 35, by reacting, in step A of Example 1, the furan lithium reagent with octanal in tetrahydrofuran at -78 °C.

Elemental analysis: C found 51.35 % calculated 51.27 (empirical formula: C16H23C1«0S molecular mass: 374.82) H N CI 6.17 7.40 9.47 6.18 7.47 9.46 EXAMPLE 40; N- (1 -Chloroacetyl-5-heptyl-5-methyl- 2-oxo-perhydropyrano[3,2-d]oxazol-6 -yl) acetamide Step A: N-(5-heptyl-5-methyl-2-oxo-perhydro-25 pyrano[3,2-d]oxazol-6-yl)acetamide Compound obtained from 5-methyl-5-heptyldihydropyrano-[3,2-d]oxazole-2,6-dione, which is itself obtained by catalytic hydrogenation (palladium-on-charcoal, ethyl 30 acetate, l atmosphere) by treatment with ammonium acetate (9 eq) in the presence of sodium cyanoboro-hydride (20 eq) in methanol at room temperature for one REPLACEMENT SHEET (RULE 26) 8123 hour. After concentration under vacuum, the reaction medium is diluted in an acetic acid/acetic anhydride mixture at room temperature and stirred for 10 hours. After concentration under vacuum and chromatography on 5 silica (1/4 heptane/ethyl acetate), N-(5-heptyl-5-methyl-2-oxo-perhydropyrano[3,2 d] oxazol-6-yl)acetamide is obtained, which is used in its present state in the subsequent synthesis.

Step B: N-(l-Chloroacetyl-5-heptyl-5-methyl- 2-oxo-perhydropyrano[3,2-d]oxazol-6-yl)acetamide The compound obtained in step A ,\3 treated with 2-15 chloroacetyl chloride according to the procedure described in step E of Example 4, in order to give the expected product in the form o."C a white powder.

Spectral characteristics: *H NMR, (DMSO) , 8 (ppm) : 8.5 (lH,s); 6.55 (lH,d); 6.15 (1H,d); 5.0 (1H,dd); 4.8 (2H,dd); 2.0 (3H,s); 1.9 (lH,m); 1.55 (lH,m); 1.45 (5H,m); 1.6-1.10 (10H,m); 0.85(3H,t) EXAMPLE 41; 1-Chloroacetyldihydropyrano- [3,2-d]oxazole-2,6-dione Compound obtained from 6-hydroxy-2H-pyran-3(6H) one, 30 prepared according to M. P. Georgiadis et al., Org. Prep. Proc. Int., (1992), 24(1), 95-118) according to the procedure of Example 1, step C, followed by treatment of the crude product obtained, at room temperature, in acetone for 24 hours.

Elemental analysis: (empirical formula: C8HBC1N05 molecular mass: 233.61) REPLACEMENT SHEET (RULE 26) 43 3081 % calculated 41.13 % found 41.48 C H 3.45 3.78 N 6.30 6 .00 CI .13 15.18 EXAMPLE 42: 1-Chloroacetyl 5-heptyl-5-methyldihydropyrano [3,2-d]oxazole-2,6-dione 6- (O-acetyloxime) Step A: 5-(hept-l-ynyl)-5-methyldihydro- pyrano[3,2-d]oxazole-2,6-dione 6-oxime Hydroxylamine hydrochloride (1.8 g; 0.0259 mol) and sodium acetate (3 g; 0.022 mol) are added to a solution of the diastereoisomer A of 5-(hept-l-ynyl)-5-methyl-dihydropyrano [3,2-d]oxazole-2,6-dione (1.08 g; 0.004 mol) obtained in step C of Example 1, in methanol 15 (35 ml). The reaction medium is stirred at 40°C for 12 hours. The reaction medium is then concentrated. The residue is diluted in diethyl ether and washed with water. The organic phases are dried over magnesium sulfate and then concentrated. The residue obtained is 20 taken up in diethyl ether and the desired product is precipitated from hexane. A beige-coloured powder (700 mg) is obtained, which is used in its present state in the subsequent synthesis.

Step B: N-(5-heptyl-5-methyl-2-oxo-2,3a,5,7a- The compound obtained in step A (400 mg, 1.4 mol) in an 30 acetic acid (12 ml)/acetic anhydride (40 ml) mixture is stirred in the presence of palladium-on-charcoal (80 mg) under a hydrogen atmosphere, at atmospheric pressure and at room temperature for 14 hours. The reaction medium is then filtered through Celite and 35 distilled azeotropically with toluene. A gummy residue tetrahydro-lH-pyrano[3,2-d]oxazol-6-yl)acetamide REPLACEMENT SHEET (RULE 26) ? q.,812 3 is obtained, which is crystallized from a "clieEhy] ether/pentane mixture. 240 mg of a beige-coloured powder are thus obtained, which product is used in its present state in the subsequent synthesis. The filtrate 5 consists mainly of 5-heptyl-5-methyldihydropyrano [3, 2-d] oxazole-2, 6-dione 6-(O-acetyloxime), which will be used for the preparation of the compound of Example 42.

Step C: 1-Chloroacetyl-5-heptyl-5-diethyl- dihydropyrano [3,2-d] oxazole-2, 6-dione 6-(O-acetyloxime) The compound obtained in step B is treated with 15 2-chloroacetyl chloride, in the presence of n-butyllithium under the operating conditions described in step E of Example 4.

Spectral characteristics: 2 0 XH NMR, (DMSO) , 8 (ppm) : 6 (d,lH); 4.9 (m,2H); 4.75 (d, 1H) ; 3.65 (dd,lH); 2.6 (dd,lH); 2.05 (s,3H); 1.71 (m,2H); 1.45 (s,3H); 1.25 (m,10H); 0.9 (t,3H).

EXAMPLE 43: l-Chloroacetyl-5-heptyl-5-methyl- dihydropyrano [3,2-d] oxazole-2, 6-dione 6-oxime.

Treatment of the compound obtained in step A of Example 3 0 42 with 2-chloroacetyl chloride (under the operating conditions described in step E of Example 4) leads to the expected product.

Spectral characteristics: 'H NMR, (DMSO), 8 (ppm): 11 (s,lH); 6.05 (d,lH); 4.9-4.6 (AB + m, 3H) ; 3.15 (dd, 1H) ; 2.85 (dd, 1H) ; 2.25 (m,2H); 1.65 (s,3H); 1.5-1.20 (m,10H); 0.85 (t,3H).

REPLACEMENT SHEET (RULE 26) 308123 EXAMPLE 44: 6-Butyl-1-chloroacetyl-5-mepty1- -methyl - 6 -hydroxy tetrahydropyrano-[3,2-d]oxazol-2-one Treatment of the crude product obtained in Example 11-1 with 2-chloroacetyl chloride in the presence of n-butyllithium gives a crude product which is purified by chromatography on a column of silica in order to obtain the expected product.

Spectral characteristics: XH NMR, (DMSO), 8 (ppm): 5.95 (lH,d); 4.8 (2H,dd); 4.3 (1H,q); 3.55-3.45 (lH,d); 2.60-2.55 (2H,dd); 1.8-1.2 (19H,m); 0.9 (6H,t).

EXAMPLE 45: Chloroacetyl - 5-hexyldihydropyrano - [3,2-d]oxazole-2,6-dione Step A: 1-(2-furyl)heptan-l-ol 105 ml of n-butyllithium (2.5M) .in hexane are added dropwise to a solution containing 38.2 ml (35.77 g, 525.4 mmol) of furan in 500 ml of anhydrous tetrahydrofuran, cooled to 0°C. Stirring is maintained for one hour at 0°C.

The reaction medium is then cooled to -78°C and 36.76 ml (262.7 mmol) of heptanal in anhydrous tetrahydrofuran are added dropwise. The mixture is stirred for a further one hour at -78°C. The solution is then hydrolyzed with saturated aqueous sodium chloride solution and then extracted with pentane. The organic phases collected are dried over magnesium sulfate and then filtered and concentrated. An orange oil is obtained (38.6 g), corresponding to the expected product, and is used in its present state in the subsequent synthesis.

REPLACEMENT SHEET (RULE 26) - 46 308123 Step B: 1-Chloroace tyl-5-hexyldihydropyrano-[3,2-d]oxazole-2,6-dione The compound of step A is subjected to the procedures of steps B and C of Example 1 in order to give a mixture of two isomers.

The diastereoisomer A is isolated by chromatography on silica.

Rf = 0.39 (80/20 cyclohexane/ethyl acetate).

Spectral characteristics: JH NMR, (DMSO), 8 (ppm): 6.22(d,lH); 4.85-4.72 (dd,2H); 4.91 (m,lH); 4.07 (dd,lH); 3.0 (dd,lH) ; 2.9 (dd,1H); 15 1.75 (m,1H); 1.6 (m,1H); 1.45-1.15 (m,8H); 0.83 (t,3H).

EXAMPLE 46: 1-Chloroacetyl-5-hexyldihydro- pyrano[3,2-d]oxazole-2,6-dione Second diastereoisomer obtained during the synthesis of the compound of Example 45.

Rf = 0.33 (eluent: 80/20 cyclohexane/ethyl acetate) Spectral characteristics: 'H NMR, (DMSO), 8 (ppm): 5.98 (d,lH); 4.82-4.72 (dd,2H); 4.78 (m,lH); 4.2 (dd,1H); 3.0 (dd,1H); 2.85 (dd,1H); 1V7 (m, 1H); 1.55 (m,1H); 1.45-1.15 (m,8H); 0.83 (t,3H).

EXAMPLE 47: (3aS, 5R, 7aS) -l-chloroacetyl-5-trityloxy-methyldihydropyrano [3,2-d] oxazole-2,6-dione REPLACEMENT SHEET (RULE 26) § 47 308123 °=< N N Compound obtained by working according to the procedure described in steps B and C of Example 1, starting with 5 (li?)-1-(2-furyl)-2-trityloxyethanol (described in M. P. Georgiadis et al., Pol. J. Chem, (19.90), 64, 823-826).

Spectral characteristics: XH NMR, (DMSO), 8 (ppm): 7.5-7.2 (15H,m); 6.4 (lH,d); 10 5.05 (lH,m); 4.8 (2H,AB); 4.4 (lH,t); 3.35 (2H,d); 3.2 (1H,d); 3.0 (lH,d).

EXAMPLE 48: 2-(l-Chloroacetyl-2,6-dioxodihydro-15 pyrano[3,2-d]oxazol-5-yl)ethyl acetate Compound obtained by working according to the procedure described in step C of Example 1, starting with ethyl (6-hydroxy-3-oxo-3,6-dihydro[2 H] pyran-2-yl)acetate 20 (prepared according to Sato et al., J. Org. Chem., (1989), 54, 2085-2091).

EXAMPLE 49: Benzyl-[(1-chloroacetyl-5-heptyl-25 6 - hydroxy- 5 -methyl - 2 -oxotetrahydro- Compound obtained according to the procedure described 30 in Example 10, by reacting 6-(5-heptyl-5-methyl-tetrahydropyrano[3,2-d] oxazol-2-one] spiro-2'-oxirane with sodium methanedithiolate in dimethylformamide and pyrano [3,2-d] oxazol-6-yl)methyl]methyl-sulfonium [sic] REPLACEMENT SHEET (RULE 26) • ... 308123 then with benzyl chloride, in the presence of silver bromide in trichloromethane, before carrying out the chloroacetylation reaction according to the procedure described in step E of Example 4.

EXAMPLE 50: Benzyl-[(1-chloroacetyl-6-chloroacetyl-carbamoyloxy-5-heptyl-5-methyl-2-oxo-tetrahydropyrano[3,2-d]oxazol-6-yl)-10 methyl]methylsulfonium [sic] Compound obtained by treatment of the compound of Example 49 with 2-chloroacetyl isocyanate under the operating conditions described in Example 30.

EXAMPLE 51: 2-[(l-Chloroacetyl-5-heptyl-6-hydroxy- -methyl-2-oxote ^ahydro-pyrano [3,2-d] oxvtzol-6-yl)methyl] -20 1,3-dihydrobenzo[c]thienyllum [sic] 6- (5-Heptyl-5-methyl-tetrahydropyrano[3 .-2-d] oxazol-2-one] spiro-2'-oxirane, obtained by catalytic hydrogenation of the compound obtained in step B of 25 Example 4, is treated with (2-mercaptobenzyl)methanol in the presence of sodium methoxide in methanol. The benzyl alcohol function is then treated with methanesulfonyl chloride in the presence of triethylamine in dichloromethane. Cyclization to the 30 dihydrobenzo[c]thiophene is finally obtained by heating to 30°C in dichloromethane. The compound thus obtained is then chloroactylated according to the procedure described in step E of Example 4.

REPLACEMENT SHEET (RULE 26) 308123 EXAMPLE 52: 1-Chloroacetyl-5-hexy1-7a-methyldihydro-pyrano[3,2-d]oxazole-2,6-dione Compound obtained according to the procedure described in Example 45, starting with 4-methyl-2-bromofuran (prepared according to M. E. Maier et al., Tet. Lett., (1991), 32, 53-56) and heptanal.

EXAMPLE 53: 1-Chloroacety1-5-hexy1-7-methyldihydro-pyrano[3,2-d]oxazole-2,6-dione Compound obtained by working according to the procedure 15 described in Example 41, starting with 2-hexyl-6-hydroxy-4-methyl-6H-pyran-3-one (obtained by oxidative rearrangement of 1-[2-(3-methylfuryl)]he -dn-l-ol prepared according to Sato et al., J. Org. Chem., (1989), 54, 2085-2091).

EXAMPLE 54; 1 -Chloroacetyl-7-methoscy-5-methyldihydropyrano [3,2-d] oxazole-2, 6-dione By working as described for Example 53, starting with 6-hydroxy-4 -methoxy-2-methy1-6 W-pyrane-3-one (obtained by oxidative rearrangement of 3-methoxyfuran-2-yl-methanol prepared according to P. A. Weeks et al., J. Org. Chem., (1980), 45, 1109)[lacuna].

EXAMPLE 55; 3a-Benzyloxymethyl-l-chloroacetyldi-hydropyrano[3,2-d]oxazole-2,6-dione By working as described in Example 1, steps B and C, starting with 2-benzyloxymethyl-5-hydroxymethylfuran (prepared according to O. Achmatowicz et al., REPLACEMENT SHEET (RULE 26) 308123 Tetrahedron, (1982), 38, 3507-3513) the title product is obtained.

By working ir a similar manner to that of the examples 5 described above, the following compounds were obtained: EXAMPLE 561 3a-Benzyloxymethyl-1-chloroacetyl-carbamoyl-5,7a-dimethyl-5-heptyldihydro-pyrano[3,2-d]oxazole-2,6-dione EXAMPLE 57; 6-11-Chioroacety1-3 a-dimethylaminoethyl• 7-me thyl-5,5-diphenyltetrahydro-pyrano[3,2-d]oxazol-2-one]spiro-2'-oxirane EXAMPLE 58; 6-Acetylamino-1-chloroacetyl-5-heptylperhydropyrano[3,2-d]oxazol-2-one EXAMPLE 591 EXAMPLE 601 6-Acety1amino-1-chloroacety1-5-hepty1-7a-methylperhydropyrano[3,2-d]oxazol-2-one 6-Benzyloxy-3a-benzyloxymethyl- 1-chloroace tylcarbamoyl-5-heptyl- -me thyl tetrahydropyremo [3,2-d] oxazol- 2-one EXAMPLE 61? EXAMPLE 62; EXAMPLE 63: 1- (2-Chloropropanoyl) -5-heptyl-dihydro [3,2 - d] oxazole-2,6-dione 6-Butyl-1-chloroacetylcadbamoyl-5-(2• chloro-1-chloroacetylcarbamoyl-oxyheptyl)-5-methyltetrahydropyrano-[3,2-d]oxazol-2-one 1-Chloroacetyl-5,7-dime thyl-6-methyl • amino-5-(3-pentyloxiran-2-yl)tetrahydropyrano [3,2 - d] oxazol - 2 - one REPLACEMENT SHEET (RULE 26) 3081 EXAMPLE 64: 1-Chloroacetylcarbamoyloxy-6-diethylamino-5-heptyltetra-hydropyrsmo[ 3,2 - d]oxazol-2-one EXAMPLE 65: 6-Benzylidene-5-(3-chloroacetyl-carbamoyloxypropyl) -1-cinnamoyl-5-methyldihydropyrano [3, 2-d] oxazol-2-one REPLACEMENT SHEET (RULE 26) 52 3081 PHARMACOLOGICAL STUDY EXAMPLE A: Study of the auiti-proliferative activity of the compounds of the invention.

Three cell lines were used: 1 mouse leukemia, L1210, 1 human epidermoid carcinoma, A431, 1 primary culture of endothelial cells from pig The cells are cultured in RPMI 1640 complete culture medium containing 10% foetal calf serum, 2 mM glutamine, 50 units/ml of penicillin, 50 (ig/ml of 15 streptomycin and 10 mM of HEPES (pH = 7.4).

The cells are divided among microplates and exposed to the cytotoxic compounds.

The cells are then incubated for two days (L1210) , 3 20 days (CEAP) and 4 days (A431) . The number of viable cells is then quantified by a colorimetric test, the Microculture Tetrazolium Assay (Carmichael J., DeGraff W. G., Gazdar A. F., Minna J. D. and Mitchell J. R., Evaluation of a tetrazolium-based semiautomated 25 colorimetric assay: assessment of chemosensitivity testing, Cancer Res., 47, 936-942, (1987)).

The compounds of the present invention showed an antiproliferative activity on these three cell lines. For 3 0 example, the IC50 values (concentrations of compound which inhibit the proliferation of the treated cells by 50%) are, depending on the cell lines, from 3 to 10 times lower than those of fumagillin.

EXAMPLE B: Inhibition of the neovascularization of aorta, CEAP the chorioallantoid membrane of chick embryo REPLACEMENT SHEET (RULE 26) 3081 This test is performed with chick embryos as described previously (Crum R. , Szabo S. and Folkman J., Science, (1985) , 230, 1375-1378) . The fertilized eggs (DO) are incubated at 37 °C. A pocket of air is created by taking 5 1 ml of albumin (D3) and a window is then cut into the shell (D4) and the vitelline membrane is removed in order to release the chorioallantoid membrane (CAM). The test products are dissolved in ethanol and placed on methylcellulose discs which are dried and deposited 10 on the CAM on day 6. Between 8 and 16 eggs are used per group. The zone situated around the disc is then examined 48 hours later. The eggs having an avascular zone greater than 4 mm in diameter are counted and the results are expressed as a percentage of eggs having an 15 avascular zone. The results obtained for each of the compounds of the invention are indicated in Table 1 below: - Table 1 - Inhibition of the neovascularization of the chorioallantoid membrane of chick embryo Compound % of eggs having an avascular zone Example 1 70 ± 10 Example 9 t"-+1 o\ 00 Example 11-1 87 ± 6 Example 15 65 ± 15 Example 16 85 ± 5 Example 17 73 ± 8 Example 21 71 ± 8 Example ?6 71 ± 1 Example *(1 86 ± 4 Example 3'2-1 76 ± 13 Example 33 90 ± 4 Example 34 75 ± 15 REPLACEMENT SHEET (RULE 26)

Claims (14)

- 54 - EXAMPLE C: Antitumor activity The antitumor activity of the compounds of the invention were studied according to the procedure 5 described by R. I. Geran et al., Cancer Chemiotherapy Reports, (1972), Part 3, pages 3 sqq. Mice are divided randomly into treated groups (11 mice/group) and a control group of 40 mice. 10 Tumor fragments were implanted on day 0 (subcutaneous implant) . The test compounds were administered for 12 days (day 1 to day 12) via the i.p. route. The average weight of the tumor was determined on day 15 13 after implantation. The percentage of inhibition was calculated according to the formula: 20 For example, the compound of Example 31 showed an inhibition of 79% at a dose of 120 mg/kg. 25 Preparation formula for 1000 tablets containing 50 mg doses. % inhibition 100 — average weight of the tumor (treated group) average weight of the tumor (control group) EXAMPLE D: PHARMACEUTICAL COMPOSITION: TABLETS Compound of Example 31 Wheat starch 50 g 15 g 30 Corn starch Lactose Magnesium stearate ... Silica Hydroxypropylcellulose 15 g 65 g 2 g 1 g 2 g REPLACEMENT SHEET (RULE 26) WO 96/33999 CLAIMS - 55 - PCT/FR96/00629 308123

1. Compounds of general formula (I): in which: • Rx is chosen from the radical R and the radical -NH-CO-R, • R is chosen from an amino radical and an alkylamino, dialkylamino, alkyl, alkenyl, alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy or heteroaryloxy radical, • R2 is chosen from hydrogen and an alkyl radical, • R3 is chosen from hydrogen, an alkyl radical, a hydroxyl radical, an alkoxy radical, an aryl radical, an arylalkyl radical, a radical -(CH2)n-OR8 and a radical - (CH2)n-NR8R9, • R4 represents hydrogen or else forms a bond with Y, • Rs is chosen from hydrogen, an alkyl radical, an aryl radical, an arylalkyl radical, a heteroaryl radical and a heteroarylalkyl radical or else forms a bond with Y, • Rs is chosen frcrr. hydrogen, an alkyl radical an alkyl epoxy radical, an arylalkyl radical, an arylalkyl epoxy radical, an alkenyl radical, an alkynyle radical, an alkoxycarbonyl radical, a carboxyl radical, an aryl radical and a heteroaryl radical. REPLACEMENT SHEET (RULE 26) 3081 R7 is chosen from hydrogen, an alkyl radical, an arylalkyl radical, a radical - (CH2)n-ORB, a radical - (CH2)n-0-C0-R8 and a radical - (CH2)n-NR8R9, R8 and R,, which may be identical or different, are chosen, independently of each other, from hydrogen, an alkyl radical, an aryl radical and an arylalkyl radical, n takes a value chosen from 1, -1, 3 and 4, X and Y are such that: ♦ X is chosen from hydrogen, a hydroxyl radical, an alkoxy radical, an amino radical, an alkylamino radical, a dialkylamino radical, a radical -0-CO-R'! and a radical -NH-CO-R'x, where R'x has the same definition as Rx above and Y represents hydrogen, or alternatively, ♦ X represents hydrogen and Y forms a bond with R4 or Rs, or alternatively, ♦ X and Y together form a methylene group, a group =CH-alkyl, a group =CH-aryl or a group =CH-arylalkyl, or alternatively, ♦ X and Y together form an oxo group, or alternatively, ♦ X and Y together form an oxirane ring with the carbon atom which bears them, or alternatively. ♦ X and Y together form a hydroxyimino radical or a radical =N-0-C0-R'x, where R' x has the same definition as Rx defined above, or alternatively, REPLACEMENT SHEET (RULE 26) 308123 - 57 - ♦ X is chosen from an alkyl radical, an arylalkyl radical and a radical ©A -chtsx , Rb and Y is chosen from hydrogen, a hydroxyl group and a radical O-CO-NH-CO-R' where R' has the same definition as R defined above, or forms a bond with R4 or R5, • R, and R^ which may be identical or different, are chosen, independently of each other, from an alkyl radical, an aryl radical, an arylalkyl radical, a heteroaryl re.dical and a heteroarylalkyl radical, or alternatively form, together with the sulfur atom which bears them, an optionally substituted radical chosen from thienyl, 1,3-dihydrobenzo[c]thien-2-yl, 2,3-dihydrobenzo[b]thien-l-yl, perhydrobenzo[c]thien-2-yl and perhydrothienyl, it being understood that: the term "alkyl" included in the alkyl, alkylamino, dialkylamino, arylalkyl, arylalkyl-epoxy, heteroarylalkyl and alkylepoxy radicals denotes a radical whose saturated hydrocarbon chain contains from 1 to 10 carbon atoms, in a straight or branched chain, and is optionally substituted, the term "alkenyl" denotes a radical containing from 2 to 10 carbon atoms in a straight or branched chain, optionally substituted, and containing unsaturation .in the form of a double bond, the term "alkynyl" denotes a radical containing from 2 to 10 carbon atoms in a straight or branched chain, optionally substituted, and REPLACEMENT SHEET (RULE 26) 308123 58 containing unsaturation in the form of a triple bond, the term "alkoxy" included in the alkoxy and alkoxycarbonyl radicals denotes a radical whose saturated hydrocarbon chair, contains from 1 to 10 carbon atoms, in a straight or branched chain, and is optionally substituted, the term "aryl" included in the aryl, arylalkyl, aryloxy and arylalkylepoxy radicals denotes an optionally substituted radical chosen from phenyl and naphthyl, the term "heteroaryl" included in the heteroaryl, heteroaryloxy and heteroarylalkyl radicals denotes an optionally substituted radical chosen from furyl, thienyl, thiazolyl, imidazolyl, thiadiazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, indolyl and isoindolyl, the term "optionally substituted" means that the radicals thus qualified may optionally be substituted with one or more chemical moieties chosen from: hydroxy, O-CO-R'i, where R'j has the same definition as Rx defined above, alkoxy, - alkyl, alkenyl, alkynyl, epoxy, alkylthio, halogen, chosen from fluorine, chlorine, bromine and iodine, trihalomethyl, and that REPLACEMENT SHEET (RULE 26) 308123 - 59 - nitro, amino, alkylamino and dialkylamino, carboxyl, alkoxycarbonyl, alkylcarbonyl alkoxycarbonylalkyl, carboxylalkyl, aryl, and heteroaryl,

2. Compounds according to Claim 1, for which X and Y together form an oxo group, their possible geometric isomers and optical isomers, in pure form or in the form of a mixture, their possible pharmaceutically acceptable addition salts with an acid, and their possible S-oxides, N-oxides or quaternary ammonium salts.

3. Compounds according to Claim 1, for which X and Y together form, with the carbon atom which bears them, an oxirane ring, their possible geometric isomers and optical isomers, in pure form or in the form of a mixture, their possible pharmaceutically acceptable addition salts with an acid, and their possible S-oxides, N-oxides or quaternary ammonium salts.

4. Compounds according to Claim 1, for which Y represents hydrogen and X represents a radical -O-CO-R'j, where R'a is as defined in Claim 1, their possible, geometric isomers and optical isomers, in pure form or in the form of a mixture, their possible pharmaceutically acceptable addition salts with an acid, and their possible S-oxides, N-oxides or quaternary ammonium salts.

5. Compound according to Claim 1, which is 1-chloroacetyl-5-heptyldihydropyrano[3,2-d]oxazole-2,6-dione, and its optical isomers in pure form or in the form of a mixture.

6. Compound according to Claim 1, which is 1-chloroacetylcarbamoyl-6-chloroacetylcarbamoyloxy- REPLACEMENT SHEET (RULE 26) •< .... 3081 5-(5-phenylpent-1-ynyl)-5-methyltetrahydropyrano-[3,2-d]oxazol-2-one, and its optical isomers in pure form or in the form of a mixture.

7. Compound according to Claim l, which is 1-chloroacetylcarbamoyl- 6 -chloroacetylcarbamoyloxy- 5-heptyl-5-methyltetrahydropyrano[3,2-d]oxazol-2-one, and its optical isomers in pure form or in the form of a mixture.

8. Compound according to Claim 1, which is l-chloroacetyl-5-(l-hydroxy-2-chloro-5-phenylpentyl)-5-methyltetrahydropyrano[3,2-d] oxazol-2-one]spiro- 2'-oxirane, and its optical isomers in pure form or in the form of a mixture.

9. Process for the preparation of the compounds of formula (I) according to Claim 1, characterized in that the furyllithium of formula (II) is treated with the compound of formula (III): JcC u (l,) Y' <'»> R7^o u ° where R2, R3, R5, Rs and R7 are as defined in Claim 1, in a polar aprotic solvent, at a suitable temperature, chosen within a range from -100°C to 30°C, in order to lead to the furylcarbinol of formula (IV): (IV) in which R2, R3, R5, R6 and R7 are as defined above, which compound, when subjected to oxidation, in the presence of an acid, in a suitable solvent, at a REPLACEMENT SHEET (RULE 26) 61 'SO 81 temperature of between 0°C and 22°C, is rearranged into the pyranone of formula (V): R. in which R2, R3, Rs, R£ and R7 are as defined above, which pyranone of formula (V) is subjected to the action of 2-chloroacetyl isocyanate in order to obtain the dihydropyrano[3,2-d]oxazole-2, 6-dione of formula in which R2, R3, Rs, Rs and R7 are as defined above, this being a specific case of the compounds of formula (I) according to Claim 1 in which Rx represents the -CH2-C1 radical, X and Y together form an oxo group and R4 represents hydrogen, which compound of formula (IJ may be cleaved, under the action of an alcohol, or of a weak base, to a compound of formula (VI): (V) CI Rt 4 (V!) where R2, R3, R5, R6 and R7 are as defined above, REPLACEMENT SHEET (RULE 26) - 62 - toe in which the oxo group borne by carbon atom 6 is subjected to various standard reactions, in order to lead to the compound of formula (Id) which is finally subjected to the action of a halide of formula R-CO-X, where R is as defined in Claim 1 and X represents a halogen atom, or alternatively to the action of an isocyanate of formula R-CO-NCO, where R is as defined in Claim 1, in order to obtain, respectively, the compounds of formulae (2b) and (Ic) : <?, °" ^ w o °=< NnA/-Y 0" -Q-*7 n. (W in which R2, R3, R5, Rs and R7 are as defined above, and R4, X and Y are as defined in Claim 1, the set of compounds of formula (Ib) and (Ic) forming the set of compounds of formula (I) which are purified, where appropriate, by a standard purification technique, whose geometric isomers and optical isomers are separated, if desired, by a standard separation technique, and which are converted, where appropriate, into their N-oxides, S-oxides, their pharmaceutically acceptable addition salts with an acid or into their quaternary ammonium salts.

10. Pharmaceutical compositions containing as active principle at least one compound according to any one of Claims 1 to 8, alone or in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles.

11. Pharmaceutical compositions according to Claim 10, Intellectual Property Office of NZ 2 6 MAY 1998 Received o / .} useful in the treatment of complaints due to or associated with angiogenesis disorders.

12. A compound of general formula (I) according to claim 1 substantially as herein described with reference to the accompanying drawings.

13. A process according to claim 9 substantially as herein described with reference to the accompanying drawings.

14. A pharmaceutical composition according to claim 10 substantially as herein described with reference to the accompanying drawings. END OP CLAEMS Intellectual Property Office of NZ 2 6 MAY 1998 RECEIVED