WO1996033999A1

WO1996033999A1 - NOVEL SUBSTITUTED TETRAHYDROPYRANO[3,2-d]OXAZOLONES, METHOD FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Info

Publication number: WO1996033999A1
Application number: PCT/FR1996/000629
Authority: WO
Inventors: David C. Billington; Françoise PERRON-SIERRA; Ghanem Atassi; Alain Pierre; Michael Burbridge; Nicolas Guilbaud
Original assignee: Adir Et Compagnie
Priority date: 1995-04-27
Filing date: 1996-04-24
Publication date: 1996-10-31
Also published as: NO974870D0; JPH11504029A; EP0822936A1; NO974870L; FR2733499A1; CA2219571A1; NZ308123A; AU5766496A; FR2733499B1; CN1185156A

Abstract

Compounds of general formula (I), wherein R1, R2, R3, R4, R5, R6, R7, X and Y are as defined in the description, are disclosed and are useful as medicaments.

Description

NEW TETRAHYDROPYRANO [3,2-d] SUBSTITUTED OXAZOLONES,

THEIR PREPARATION PROCESS AND THE COMPOSITIONS

PHARMACEUTICALS THAT CONTAIN THEM

The present invention relates to new compounds having a tetrahydropyrano [3,2-d] oxazolone structure, their preparation process and the pharmaceutical compositions containing them. The compounds of the present invention find a very advantageous therapeutic use thanks to their angiogenesis inhibiting power.

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

Abnormal angiogenesis (i.e., stimulation of the growth of new blood vessels due to a pathological syndrome) is an established feature for many diseases, including diabetic retinopathy, rheumatoid arthritis, hemangiomas and growth solid tumors. Angiogenesis can also play an important role in other diseases such as coronary artery disease. In the field of oncology, the growth of solid tumors has been shown to be entirely dependent on the constant development of new vessels

REPLACEMENT SHEET (RULE tf) and that it is correlated, for the metastases of certain cancers, with the growing size of the primary tumor. (J. Folkman, New Engl. Med., 285 (1974), 1182-

1185).

Pharmaceutical treatment (i.e. using an angiogenesis inhibitor) can therefore stop the growth of primary tumors, prevent or reduce the formation of metastases, prevent the appearance of secondary tumors. Such angiogenesis inhibitors are also useful in the treatment of the previously mentioned non-neoplastic diseases in which angiogenic activity occurs. The needs of therapy require the constant development of new angiogenesis inhibiting compounds in order to obtain active ingredients that are more active, more specific and less toxic.

The prior art of the present invention is illustrated in particular by US Pat. No. 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, EP-A-354,767) but have structures of the fumagillol type.

The present invention relates to new compounds having a tetrahydropyrano [3,2-d] oxazolone structure and having a structural and pharmacological originality compared to the compounds described in the prior art.

More particularly, the subject of the present invention is the compounds of general formula (I):

in which

Ri is chosen from the radical R and the radical -NH-CO-R,

SUBSTITUTE SHEET (RULE 26) R is chosen from the amino radical, an alkylamino, dialkylamino, alkyl, alkenyl, aikoxy, aryl, arylalkyl, heteroaryl, heteroaryialkyl, aryloxy and heteroaryloxy radical,

R ₂ is chosen from hydrogen and an alkyl radical,

• R ₃ is chosen from hydrogen, an alkyl radical, the hydroxy radical, an aikoxy radical, an aryl radical, an arylalkyl radical, a - (CH ₂ ) _n -OR _e radical, and a - (CH ₂ ) radical „-NR _β R ₉ ,

• R4 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 heteroaryialkyl radical or else forms with Y a bond,

• Rβ is chosen from hydrogen, an alkyl radical, an alkylepoxy radical, an arylalkyl radical, an arylalkylepoxy radical, an alkenyl radical, an alkynyl radical, an alkoxycarbonyl radical, a carboxy radical, an aryl radical and a heteroaryl radical,

• R ₇ is chosen from hydrogen, an alkyl radical, an arylalkyl radical, a - (CH ₂ ) n-OR _β radical, a - (CH ₂ ) n-0-CO-R ₈ radical and a - ( CH ₂ ) n-NR _β R ₉ ,

• Rβ and R ₉ , identical or different, are chosen, independently of one another, 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, the hydroxy radical, an aikoxy radical, the amino radical, an alkylamino, dialkylamino radical, the radical -O-CO-RS and the radical -NH-CO-RS, where R'1 a the same definition as Ri defined above and Y represents hydrogen,

SUBSTITUTE SHEET (RULE 26) or,

* X represents hydrogen and Y forms with R4 or R ₅ a bond, or else,

* X and Y together form a methylene group, a ≈CH-alkyl group, a group = CH-aryl or a group = CH-arylalkyl, or else,

* X and Y together form an oxo group, or,

* X and Y together form an oxirane ring, with the carbon atom which carries them, or else,

* X and Y together form the hydroxyimino radical or a radical = N-0-CO-R'ι, where RS has the same definition as Ri previously defined, or else, * X is chosen from an alkyl radical, a radical arylalkyl and a radical

^R a

-CHj-s, and Y is chosen from hydrogen, the hydroxyl group and the

radical O-CO-NH-CO-R 'where R' has the same definition as R previously defined, or forms with R ₄ or R ₅ a bond,

• R _a and R _b , which are identical or different, are chosen, independently of one another, from an alkyl radical, an aryl radical, an arylalkyl radical, a heteroaryl radical and a heteroaryialkyl radical, or else form together with the sulfur atom which carries them an optionally substituted radical, chosen from thienyl, 1,3-dihydrobenzo [c] thien-2-yl, 2,3-dihydrobenzo [b] thien-1 -yle, perhydrobenzo [c] thien-2 - yl and perhydrothienyl,

Being heard that :

- The term "alkyl" included in the alkyl, alkylamino, dialkylamino, arylalkyl, arylalkylepoxy, heteroaryialkyl and alkylepoxy radicals denotes a radical in which the saturated hydrocarbon chain contains from 1 to 10 carbon atoms, in straight or branched chain, and is optionally substituted ,

SUBSTITUTE SHEET (RULE 26) the term "alkenyl" denotes a radical containing from 2 to 10 carbon atoms in a straight or branched chain, optionally substituted, and comprising an unsaturation in the form of double bond,

The term "alkynyia" denotes a radical containing from 2 to 10 carbon atoms in straight or branched chain, optionally substituted, and comprising an unsaturation in the form of triple bond,

the term "aikoxy" included in the aikoxy and alkoxycarbonyl radicals denotes a radical in which the saturated hydrocarbon chain contains from 1 to 10 carbon atoms, in straight or branched chain, and is optionally substituted,

the term "aryl" included in the aryl, arylalkyl, aryloxy, arylalkylepoxy radicals denotes an optionally substituted radical, chosen from phenyl and naphthyl,

- the term "heteroaryl" included in the heteroaryl, heteroaryloxy and heteroaryialkyl radicals denotes an optionally substituted radical chosen from furyl, thienyl, thiazolyl, imidazolyl, thiadiazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, indolyl and isoindol

and

- The term "optionally substituted" means that the radicals thus qualified may optionally be substituted by one or more chemical entities chosen from:

- hydroxy,

- O-CO-R'i, where R'i has the same definition as Ri previously defined,

- aikoxy,

- alkyl, alkenyl, alkynyia, - epoxy,

- alkylthio,

- halogen, chosen from fluorine, chlorine, bromine and iodine,

REPLACEMENT LIGHT (* I ^M > - trihalomethyl,

- nitro, amino, alkylamino and dialkylamino,

- carboxy,

- alkoxycarbonyl, - alkylcarbonyl,

- alkoxycarbonylalkyie,

- carboxyalkyl,

- aryle, and

- heteroaryl,

their possible geometric isomers and optical isomers, in pure form or in the form of a mixture, their optional addition salts with an acid, which are pharmaceutically acceptable, as well as their possible S-oxides, N-oxides or quaternary ammonium salts.

The present invention also extends to the process for preparing the compounds of formula (I) characterized in that the furyllithium of formula (II) is treated with the compound of formula (III):

where R ₂ , R ₃ , R ₅ , Rβ and R ₇ are as defined above,

in polar aprotic solvent, tetrahydrofuran for example, at an appropriate temperature, chosen from a range from -100 ° C to 30 ° C, preferably at -78 ° C, in order to lead to furylcarbinol of formula (IV):

in which R ₂ , R ₃ , R ₅ , Rβ and R are as defined above,

which, subjected to oxidation, for example in pyridinium chlorochromate, N-bromosuccinimide, or tert-butyl hydroperoxide, in the presence of an acid, such as camphorsurfonic acid or metachloroperbenzoic acid, in a solvent

SUBSTITUTE SHEET (RULE 26) suitable, such as dichloromethane or tetrahydrofuran, at a temperature between 0 ° C and 22 ° C, is rearranged into pyranone of formula (V):

in which R ₂ , R ₃ , R ₅ , Re and R ₇ are as defined above,

pyranone of formula (V) which is subjected to the action of 2-chloroacetyl isocyanate in order to obtain the dihydropyrano [3,2-d] oxazole-2,6-dione of formula (l _a ):

in which R ₂ , R ₃ , R ₅ , Rβ and R ₇ are as defined above,

special case of the compounds of formula (I) where Ri represents the radical -CH ₂ -CI, X and Y together form the oxo group and R ₄ represents hydrogen,

compound of formula _(a) which can be cleaved under the action of an alcohol, such as methanol, or a weak base, a compound of formula (VI):

where R ₂ , R ₃ , R ₅ , Rβ and R ₇ are as defined above,

and which are subjected to the reactions presented in the following reaction schemes I, II and III:

- Reaction scheme I -

SUBSTITUTE SHEET (RULE 26)

The reactions presented in reaction schemes (I), (II) and (III) were thus carried out:

Reaction 1: the reduction of the ketone function to alcohol is carried out in an appropriate solvent, tetrahydrofuran for example, at low temperature, from -78 ° C to 20 ° C, the reducing agent being chosen from the hydrides usually used for this type reduction. A reducing agent which is particularly suitable in the present reaction is lithium triethylborohydride.

Reaction 2: The etherification of the alcohol function is carried out according to conventional methods known to those skilled in the art. For example, the alcohol, treated with a base, such as sodium hydride, is subjected to the action of an alkyl halide.

SUBSTITUTE SHEET (RULE 26) 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 dehydration, according to conventional techniques, for example by heating in the presence of paratoluenesulfonic acid in benzene.

Reaction 4: the hydrogenation reactions are carried out conventionally in the presence of catalytic quantities of palladium and hydrogen, at atmospheric pressure or under low pressure, at a temperature between 10 ° C. and 80 ° C. The preferred operating conditions for the catalytic hydrogenations of the present invention are those where hydrogen is at atmospheric pressure, and at room temperature, the reactions being continued until complete disappearance of the compound to be hydrogenated.

Reaction 5: the 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 alcoholate conventionally obtained from alcohol that you want to esterify.

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

Reaction 7: the ketone function is here subjected to a nudeophilic attack under the conditions known to the person skilled in the art, for example attack by an afl yllithium or by an aiylalkyllithiurn, where the terms alkyl and arytalkyi are as defined above

- Reaction scheme II -

SUBSTITUTE SHEET (RULE 26)

Reaction 8: the transformation of the ketone function into an amino function is obtained by treatment with ammonium acetate (to obtain a primary amine), with an amine of formula H ₂ NAIk (to obtain a secondary amine) or with an amine of formula HNAlkAlk ^* (to obtain a tertiary amine), where Alk and AK each represents one alkyl chain as defined above The reaction is carried out in the presence of sodium cyanoborohydride, in polar protic solvent, in alcoholic solvent for example , in methanol or tethanol.

Reaction 9: the reaction with hydroxylamine hydrochloride and sodium acetate provides the expected oxime. The reaction medium is an aprotic polar medium, preferably alcoholic, methanol or ethanol for example. The reaction temperature is chosen, depending on the solvent used, in a range from 20 ° C to 80 ° C, 40 ° C for example in methanol.

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

SUBSTITUTE SHEET (RULE 26) Reaction 11: The amino function is treated as described in reactions 5 or 6.

- Reaction scheme III -

Reaction 12: The compound of formula (VI) is used in a Wittig reaction under the action of a compound of formula Ph ₃ P = CH ₂ , to obtain the compound of formula (XXIV), or under action of a compound of formula Ph ₃ P = CH-A where A represents alkyl, aryl or arylalkyl as defined above. This reaction is carried out in tetrahydrofuran at a temperature between 60 ° C and 70 ° C, the phosphonium ylides being obtained by the action of potassium tθrtiobutytate.

Reaction 13a: the spro-epoxy function is obtained by the action of dimethylsulfide ylide on the compound of example (VI).

Reaction 13b: the sp / ro-epoxide function is obtained by the action of metachloroperbenzoic acid in dichloromethane, at 0 ° C.

SUBSTITUTE SHEET (RULE 26) Reaction 14: The attack on the epoxide is carried out with a compound of formula R _a SNa, where R _a is as defined above, in an appropriate solvent, for example dimethylformamide. A second attack is then carried out with a halide of formula R _b -X where R _b is as defined above and X represents a halogen atom, attack carried out in the presence of silver bromide in trichloromethane. In the case where R _a and R _b together form a cycle, the reaction f R-SNa will be carried out in one step using a compound of formula

V ^ R _b --X

All the compounds of formula (VI) to (XXIX) forming the compound of formula (I) which is finally subjected 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 the reaction § defined above, or else to the action of an isocyanate of formula R-CO-NCO, where R is as defined above, in the operating conditions described for reaction 6 defined above. These reactions are explained by the following diagram:

where R, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , X and Y are as defined above,

all of the compounds of formula (I _b ) and (I _c ) forming all of the compounds of formula (I) which are purified if necessary by a conventional purification technique, from which we separate if desired geometric isomers and optical isomers by a conventional separation technique which is converted, where appropriate, into their N-oxides, S-oxides, their pharmaceutically acceptable acid addition salts or their salts of 'quaternary ammonium.

The compounds of the present invention can also be prepared from a compound of formula (II ¹ ):

SUBSTITUTE SHEET (RULE 26)

where R ₂ , R ₃ , Rs and R ₇ are as defined above,

on which an Irthian of formula (III ') is reacted:

in which R ₆ is as defined above, in the operating configurations described for the reaction of the compound of formula (II) with the compound of formula (III),

The compounds of formula (I) for which R ₆ represents an alkyl, alkenyl, alkynyia or alkyiepoxy radical can be advantageously obtained according to the following synthetic scheme:

where R ₂ , R ₃ , R ₅ and R ₇ are as defined above and R ' ₆ represents an alkyl radical or an arylalkyl radical, the alkyl chain comprising from 1 to 8 carbon atoms.

The radicals -CO-NH-CO-R and -CO-NH-CO-R ', where R and R' are as defined above, when they replace the compounds of formula (I) can advantageously be selectively cleaved into radicals -CO-NH ₂ . This cleavage reaction is preferably carried out on a silica column, by chromatography

SUBSTITUTE SHEET (RULE 26) liquid (HPLC), on RP18 column for example, or under controlled acid or basic conditions.

In general, the separations of any geometric or optical isomers of the compounds obtained at each of the stages of the syntheses described above may be carried out at any time deemed appropriate by those skilled in the art. Similarly, depending on the degree of stability of the substituents carried by the compounds, the various reactions presented above may be carried out in a different order from that presented in the present invention and deemed more suitable by those skilled in the art.

The compounds of formula (I) have interesting pharmacological properties. Indeed, these compounds are powerful angiogenesis inhibitors which have the advantage of presenting, compared to the reference compounds, a much less general toxicity. They therefore have an excellent therapeutic index. These compounds thus find a therapeutic application as anti-tumor agents, in the inhibition of the formation and the growth of metastases, as well as in the treatment of diabetic retinopathy, rheumatoid arthritis, hemangiomas and arterio-coronary diseases, and more generally in conditions due to or related to angiogenesis disorders.

A subject of the present invention is also pharmaceutical compositions containing the compounds of formula (I), their possible optical and / or geometric isomers or their optional addition salts with a pharmaceutically acceptable acid, alone or in combination with one or more excipients or inert and non-toxic vehicles. Among the pharmaceutical compositions according to the invention, particular mention will be made of those which are suitable for oral, parenteral, nasal, rectal, perlingual, transdermal, ocular or respiratory administration, and in particular simple or coated tablets, sublingual tablets, capsules, suppositories, creams, ointments, dermal gels, patches, injectable or drinkable preparations, aerosols, eye or nasal drops. The useful dosage varies according to the age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated treatments and ranges between 0.01 and 1 g per day, in one or more administrations.

^{HUU DE} «« LA EMENT (RULE 26) The following examples illustrate the invention but do not limit it in any way. The starting materials are known or prepared from known procedures.

EXAMPLE 1: 1-Chloroacetyl-5- (hepM-ynyl) -5-methyl-dihydropyrano

[3,2-d] oxazole-2,6-dione

Step A: 8- (2-furyl) non-6-yl-8-ol

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 are added dropwise 46.95 ml of n-butyllithium ( 2.5M) in hexane. Stirring is continued for one hour at -78 ° C. 12.89 ml (106.7 mmol) of 2-acetylfuran in 150 ml of toluene are then added. The mixture is again stirred for one hour at -78 ° C. The solution is then hydrolyzed with a saturated aqueous solution of sodium chloride and then extracted with pentane. The organic phases collected are dried over magnesium sulphate then filtered and concentrated. 22 g of a brown liquid, corresponding to the expected product, are obtained and used as such subsequently.

Step B: 2- (heptyn-1-yl) -2-methyl-3-oxo-dihydro [2f yran-6-ol

To a solution containing 10 g (48.4 mmol) of the compound obtained in the previous step in 750 ml of a tetrahydrofuran / water mixture (2: 1) cooled to 0 ° C, are added 8.62 g (48, 4 mmol) of N-bromosuccinimide. The mixture is stirred for one hour at 0 ° C. The reaction medium is then neutralized with a saturated aqueous solution of sodium hydrogencarbonate, then extracted with pentane. The usual treatment of the organic phases provides 11.63 g of an orange-brown liquid corresponding to the expected product, used as it is subsequently.

Step C: 1-chloroacetyl-5- (hept-1-ynyl) -5-methyl-dihydro-pyrano [3,2-d] oxazole-2,6-dione

SUBSTITUTE SHEET (RULE 26) To 10 g (45 mmol) of the compound obtained in the preceding step, in dichloromethane, under an inert atmosphere and at 0 ° C., are added 10.75 g (7.6 ml; 90 mmol) of chloroacetyl isocyanate. The reaction medium is stirred until disappearance of the starting product (reaction followed by thin layer chromatography). The solution is then hydrolyzed with a saturated aqueous solution of sodium chloride and then extracted with dichloromethane. The usual treatment of the organic phase provides, after purification by chromatography on a silica column (eluent: heptane / ethyl acetate, 4: 1), 4 g of the expected compound as well as 2.8 g of the two diastereoisomers A and B of 5- (hept-1-yn-1-yl) -5-methyl-dihydro-pyrano [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: diethyl ether / dichloromethane, 2: 1). Elementary analysis: (crude formula: CiβH∞CINOs molecular mass: 341, 79)

C H N Cl

% found 56.30 5.93 4.06 10.63

% calculated 56.23 5.90 4.10 10.37

EXAMPLE 2 1 -Chloroacetyl-5- (hept-1 -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 complete disappearance of the starting product. After filtration on celite and concentration of the filtrate under reduced pressure, 2 g of a white solid are obtained.

Elementary analysis: (crude formula: CiβH & CINOs molecular mass: 343.81) C H N Cl

% found 56.16 6.51 3.88 11, 10

% calculated 55.90 6.45 4.07 10.31

EXAMPLE 3 1-Chloroacetyl-5- (3-pentyloxiran-2-yl) -5-methyl-dihydro pyrano [3,2-d] oxazole-2,6-dione

SUBSTITUTE SHEET (RULE 26 ^ 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 is evaporated under reduced pressure and the oily residue thus obtained, azeotroped with toluene. After concentration under reduced pressure and drying under vacuum, the expected compound is obtained in the form of a lyophilisate. Elementary analysis: (raw formula:

molecular mass: 359.81)

C H N Cl

% found 53.49 6.19 3.74 9.77% calculated 53.41 6.16 3.89 9.85

EXAMPLE 4: 6 - [(1-Chloroacetyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one] -sp / ro-2 ' -oxirane (Isomer of the compound of Example 13)

Step A: 5- (hθpt-1-ynyl) -5-methyl-6-methylene-dihydropyrano [3,2-d] oxazol-2-one

To 10 g (28 mmol) of triphenylmethylphosphonium bromide suspended in 40 ml of tetrahydrofuran, 28 ml of a solution of potassium tert-butoxide (1M) in tetrahydrofuran are added. The reaction medium is heated for one hour at 60-70 ° C. The whole is then cooled to 0 ° C. and 2.5 g (9.35 mmol) of the diastereoisomer A of 5- (hept-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 with a saturated solution of sodium chloride and then extracted with ether. The usual treatment of the organic phase provides, after purification by chromatography on silica gel (eluent: heptane / ethyl acetate, 2: 1), 2.08 g of the expected compound.

Eta ^p e B: 6- [5- (hept- 1 -ynyl) -5-methy l-tetrahydropyrano [3,2-d] oxazol-2- one] -sp / n 2'-oxirane

SUBSTITUTE SHEET (RULE 26) To a solution of 1.8 g (6.8 mmol) of the compound obtained in the previous step in 230 ml of dichloromethane at 0 ° C, are added 5 g (20.5 mmol) of 70% metachloroperbenzoic acid. After returning to ambient temperature, the reaction medium is stirred for 12 hours. The solid formed is filtered and the filtrate is washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride. The usual treatment of the organic phase provides 5 g of a white solid which, purified by chromatography on silica gel (eluent: heptane / ethyl acetate, 1: 1), lead to 1.6 g of the expected compound.

Step C: 6- [5- (hept-1-enyl) -5-methyl-tetrahydropyrano [3,2-d] oxazol-2- one] -sp / ro-2'-oxirane

670 mg (2.39 mmol) are used in the hydrogenation reaction described in Example 2 to provide 660 mg of a white solid.

Step D: 6- [5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydropyrano- [3,2-d] oxazol-2-one] -sp / ro-2'-oxirane

660 mg (2.35 mmol) of the compound obtained in the previous step are oxidized under the conditions described in Example 3 to result in 650 mg of the expected compound in the form of a white powder.

Step E: 6- [1-chloroacetyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one] -sp / π> 2'- oxirane

To 200 mg (0.71 mmol) of compound obtained in the preceding step in 5 ml of tetrahydrofuran at -78 ° C., 467 μl (0.746 mmol) of n-butyllithium are added. After half an hour of stirring, 84 mg (0.746 mmol) of 2-chloroacetyl chloride are added. After 10 minutes of stirring, the reaction medium is hydrolyzed with a saturated solution of sodium chloride, then extracted with diethyl ether. The usual treatment of the organic phase provides 140 mg of a white solid corresponding to the expected product. Rf = 0.39 (heptane / ethyl acetate, 1: 1).

SUBSTITUTE SHEET (RULE 26) Elemental analysis: (crude formula: Ci7H ₂₄ CINθ6 molecular mass: 373.84)

C H N

% found 54.23 6.48 3.59

% calculated 54.62 6.47 3.75

EXAMPLE 5 6- [1-Chloroacetylcarbamoyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one] -sp / ^' ro-2'-oxirane

Compound obtained from 2-acetylfuran and 1-heptyne according to the procedure described in Example 4, replacing in step E 2-chloroacetyl chloride with 2-chloroacetyl isocyanate. Elementary analysis: (raw formula:

molecular mass: 414.85)

C H N

% found 51.41 6.02 6.56

% calculated 51.86 6.04 6.72

By proceeding 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- [1-Cinnamoyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one] -sp / ^' ro-2' -oxirane (diastereoisomer A)

Rf = 0.34 (heptane / ethyl acetate, 1: 1). Elementary analysis: (raw formula:

molecular weight: 427.50)

C H N

% found 66.84 6.89 3.13

% calculated 67.43 6.84 3.28 EXAMPLE 7 6- [1 -Cinnamoyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one] -sp / ro-2'-oxirane (diastereoisomer B)

Rf = 0.4 (heptane / ethyl acetate, 1: 1).

Elementary analysis: (raw formula:

molecular weight: 427.50)

C H N

% found 66.85 6.80 3.29

% calculated 67.43 6.84 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, and using in step A the appropriate alkyne.

EXAMPLE 8 6- [1 -Chloroacetyl-5- (1-hydroxy-2-chloro-heptyl) -5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one] -sp / π 2'- oxirane

Elementary analysis: (raw formula:

molecular weight: 410.30)

C H N Cl

% found 49.69 6.13 3.29 17.65

% calculated 49.77 6.14 3.41 17.28

EXAMPLE 9:

methyl-tetrahydropyrano [3,2d] oxazol-2-one] -sp / ro-2'-oxirane

Elementary analysis:

(gross formula: C _∑ nH CbNOe molecular mass: 458.34) CHN Cl

% found 54.45 5.62 2.70 17.08

% calculated 54.17 5.46 3.01 16.75

EXAMPLE 10 6- [1-Chloroacetyl-5-heptyl-5-methyl-tetrahydropyrano

[3,2-d] oxazol-2-one] -sp / ro-2'-oxirane

SUBSTITUTE SHEET (RULE 26) Compound obtained according to the procedure described in Example 4, steps A, B and E, from 5-methyl-5-heptyl-dihydropyrano [3,2-d] oxazole-2,6-dione in step A, itself obtained by catalytic hydrogenation (palladium, barium sulphate, in ethyl acetate, 1 atmosphere) of the diastereoisomer A of 5- (hept-1-ynyl) -5- methyl-dihydropyrano- [3 , 2-d] oxazole-2,6-dione obtained in Example 1. Elemental analysis: (crude formula: Ci7H ₂₆ CIN0 ₅ molecular weight: 359.85)

C H N Cl

% found 56.62 7.20 3.78 10.51

% calculated 56.74 7.28 3.89 9.85

EXAMPLE 11-1: 1-Chloroacetyl-5-heptyl-dihydro-pyrano [3,2-d] oxazole-2,6-dione (Isomer of Example 11 -2)

5 g (24.5 mmol) of the compound obtained according to the procedure described in step A of Example 1 from furaldehyde and 1-heptyne, are placed in the presence of 1.5 g of Lindiar catalyst in 100 ml of benzene, under a hydrogen atmosphere. 5 g of 1- (furan-2'-yl) octan-1-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 for provide the title compound as well as the compound of Example 1 1-2. Rf = 0.39 (cyclohexane / ethyl acetate, 60:40). Elementary analysis: (raw formula:

molecular mass: 331, 79) CHN Cl

% found 54.30 6.20 4.24 10.68

% calculated 54.30 6.68 4.22 10.68

EXAMPLE 11-2: 1-Chloroacόtyl-5-heptyl-dihydropyrano- [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. Rr = 0.28 (cyclohexane / ethyl acetate, 60:40). Spectral characteristics:

SUBSTITUTE SHEET (RULE 26) ¹ H NMR, (DMSO), δ (ppm): 6 (1H, d); 4.82 (1H, d); 4.75 (1H, m); 4.72 (1H, d); 4.17 (1H, dd); 3.0-2.8 (2H, AB); 1.72 (1H, m); 1.52 (1H, m); 1.45-1.15 (10H, m); 0.82 (3H, t).

EXAMPLE 12 1-Chloroacetyl-5- [3- (3-phenylpropyl) oxiran-2-yl] -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Compound obtained according to the procedure described in examples 2 then 3, using in step A of example 1, the appropriate acetylene derivative. Elemental analysis: (crude formula: C∞HaCINOβ molecular mass: 407.85) C H N Cl% found 59.23 5.38 3.25 8.79

% calculated 58.90 5.44 3.43 8.69

EXAMPLE 13 6- [1-Chloroacetyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydro pyrano [3,2-d] oxazol-2-one] -sp / ro-2'-oxirane (Isomer of the compound of Example 4)

Step A: 5- (hept-1-enyl) -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione

The diastereoisomer A of 5- (hept-1-yn-1-yl) -5-methyl-dihydropyrano [3,2-d] - oxazole-2,6-dione, obtained in step C of the example 1, is subjected to catalytic hydrogenation according to the procedure described in Example 2.

Step B: 6- [1-chloroacetyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one] -sp / ro-2'- oxirane

1.25 g (4.7 mmol) of compound obtained in the previous step, in 15 ml of tetrahydrofuran are reacted, at 0 ° C, with dimethyl sulfide ylide, obtained from 4.92 g ( 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 with a solution saturated aqueous sodium chloride, and extracted with diethyl ether. The usual treatment of the organic phase provides 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 of Example 4.

Rf ≈ 0.35 (heptane / ethyl acetate, 1: 1).

Elemental analysis: (crude formula: Ci7H ₂ CIN0 ₆ molecular weight: 373.84)

C H N Cl

% found 54.38 6.38 3.58 9.60

% calculated 54.62 6.47 3.75 9.48

EXAMPLE 14 1-Carbamoyl-5- (3-pentyloxiran-2-yl) -5-methyl-dihydro-pyrano [3,2-d] oxazole-2,6-dione

The 5- (hept-1-ynyl) -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione diastereoisomer A obtained in step C of Example 1 is subjected to catalytic hydrogenation, epoxidation, according to the procedures described in Examples 2 and 3, then acylation with 2-chloroacetyl isocyanate, according to the procedure described in Example 5 followed by passage over silica. Spectral characteristics:

¹ H NMR, (DMSO), δ (ppm): 7.7 (1H, s); 7.3 (1H, s); 6.2 (1H, d); 4.95 (1H, m); 3.0 (4H, m); 1.8 (2H, m); 1.6-1.3 (9H, m); 0.9 (3H, t).

EXAMPLE 15 1-Chloroacetyl-5- (hept-1-enyl) -6-hydroxy-5-methyl-tetra-hydropyrano [3,2-d] oxazol-2-one

Step A: 5- (heptyn-1-yl) -6-hydroxy-5-methyl-tetrahydroρyrano [3,2-d] oxazol-2-one

210 mg (0.786 mmol) of the diastereoisomer A obtained in Example 1 are treated with 1.57 mmol of super-hydride (LiEtsBH) in tetrahydrofuran at -78 ° C. After 15 minutes of stirring, the reaction medium is successively hydrolyzed with water, a 10% aqueous solution of sodium hydroxide and then an aqueous solution

SUBSTITUTE SHEET (RULE 26) 15% hydrogen peroxide and then extracted with ethyl ether. After drying the organic phase over sodium sulfate and then concentrating under vacuum, 200 mg of the expected product in the form of a yellow oil are obtained.

Step B: 1-chloroacetyl-5- (hept-1-enyl) -6-hydroxy-5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one

The compound obtained in the preceding stage is subjected to catalytic hydrogenation according to the procedure described in Example 2, then acylated using 2-chloroacetyl chloride according to the procedure described in Stage E of the example 4. Spectral characteristics: ¹ H NMR, (DMSO), δ (ppm): 5.7 (1H, d); 5.5 (2H, m); 5.35 (1H, d); 4.85 (2H, dd); 4.45 (1H, m); 3.6 (1H, m); 2.4-2.2 (3H, m); 2.0 (1H, m); 1.5-1.3 (9H, m); 0.9 (3H, t).

EXAMPLE 16 1-Chloroacetylcarbamoyl-5- (hept-1-ynyl) -6-hydroxy-5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one

Compound obtained from the diastereoisomer A obtained in Example 1 treated with the super hydride (LiE BH) according to the operating conditions of step A of the example

15, then with chloroacetyl isocyanate, according to the procedure described in step

E of Example 4.

Spectral characteristics:

¹ H NMR, (DMSO), δ (ppm): 6.0 (1H, d); 5.45 (1H, d); 4.6 (2H, s); 4.55 (1H, m); 3.8 (1H, m); 2.4 (2H, m); 2.3-2.15 (4H, m); 1.5-1.25 (6H, m); 0.9 (3H, t).

EXAMPLE 17 1-Chloroacόtylcarbamoyl-6-chloroacetyl-carbamoyloxy-5- (hept-1-ynyl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one

Compound obtained according to the procedure of Example 16, using an excess of chloroacetyl isocyanate in the last step. Elementary analysis: (raw formula: CzoH≈CfeNaOβ molecular mass: 506.34)

CHN Cl % found 47.09 5.01 8.22 14.23

% calculated 47.44 4.98 8.30 14.00

EXAMPLE 18: 6- [1-Benzoyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one] -sp / ro-2'- oxirane

Compound obtained according to the procedure described in Example 4, replacing, in step E, 2-chloroacetyl chloride with benzoyl chloride. Spectral characteristics:

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

By proceeding according to the procedures described in Examples 1 and 2, starting from 5-phenylpentyne, the compounds of Examples 19 and 20 are respectively obtained:

EXAMPLE 19 1-Chloroacetyl-5-methyl-5- (5-phenylpenM-ynyl) -dihydro-pyrano [3,2-d] oxazole-2,6-dione

Elemental analysis: (crude formula: C20H20CINO5 molecular mass: 389.84) C H N Cl

% found 61.44 5.17 3.53 9.53

% calculated 61.62 5.17 3.59 9.09

EXAMPLE 20 1-Chloroacetyl-5-methyl-5- (5-phenylpent-1-enyl) -dihydro-pyrano [3,2-d] oxazole-2,6-dione

Spectral characteristics:

1 H NMR, (DMSO), δ (ppm): 7.5-7.3 (m, 5H); 6.0 (d, 1H); 5.65 (m, 1H); 5.35 (enlarged d, 1H); 4.97-4.7 (m, 3H); 3.0 (m, 2H); 2.6 (enlarged triplate, 2H); 2.3 (m, 2H); 1.6 (m, 2H); 1.4 (s, 3H). EXAMPLE 21 1-Chloroacetyl-5-methyl-5- (5-phenyl-pentyl) -dihydropyrano [3,2-d] oxazole-2,6-dione

Compound obtained by catalytic hydrogenation of the compound obtained in Example 19. Elemental analysis: (crude formula: C20H24CINO5 molecular mass: 393.87)

C H N Cl

% 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-dihydro-pyrano [3,2-d] oxazole-2,6-dione

Compound obtained by catalytic hydrogenation of the compound of Example 1.

Elementary analysis: (raw formula:

molecular mass: 345.83)

C H N Cl

% found 55.92 7.03 3.85 10.16

% calculated 55.57 7.00 4.05 10.25

EXAMPLE 23 1-Chloroacetyl-5- (3-methoxyprop-1-ynyl) -5-methyl-dihydro-pyrano [3,2-d] oxazole-2,6-dione

Compound obtained according to the procedure described for Example 1, from 3-methoxypropyne.

Elemental analysis: (crude formula: Cι ₃ Hι CINOβ molecular mass: 315.71) CHN Cl

% 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-1-ynyl) -5-methyl-dihydro-pyrano [3,2-d] oxazole-2,6-dione

SUBSTITUTE SHEET (RULE 26) Compound obtained according to the procedure described for Example 1, from 5-methylhexyne.

Elementary analysis: (crude formula: CiβH∞CINOs molecular mass: 341, 79)

C H N Cl

% found 56.86 5.81 4.13 10.50

% calculated 56.23 5.90 4.10 10.37

EXAMPLE 25 1-Chloroacόtyl-5- (3-methoxypropyl) -5-methyl-dihydro-pyrano [3,2-d] oxazole-2,6-dione

Compound obtained by catalytic hydrogenation of the compound of Example 23. Elemental analysis: (crude formula: Cι ₃ H ₁₈ CIN0 ₆ molecular weight: 319.74)

C H N Cl

% found 49.08 5.66 4.31 11.27% calculated 48.83 5.67 4.38 11.09

EXAMPLE 26 1-Chloroacetyl-5- (5-methylhexyl) -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Compound obtained by catalytic hydrogenation of the compound of Example 24. Elementary anal ^y : (crude formula: Cι ₆ H ₂ 4CIN0 ₅ molecular mass: 345.83)

C H N Cl

% found 55.85 7.16 3.70 10.00% calculated 55.57 7.00 4.05 10.25

Examples 27 and 28 are obtained from the compound obtained in step B of Example 4, by replacing 2-chloroacetyl chloride with 2-chloroacetyl isocyanate, according to the procedure described in step E from example 4.

SUBSTITUTE SHEET (RULE 26) EXAMPLE 27 6- [1-Chloroacetylcarbamoyl-5- (hept-1-ynyl) -5-methyl-tetra-hydropyrano [3,2-d] oxazol-2-one] -sp / ro-2'-oxirane

Elemental analysis: (crude formula: Cι _β H2aCIN2θ6 molecular mass: 398.85) CHN Cl% found 54.73 5.85 7.01 8.84

% calculated 54.21 5.81 7.02 8.89

EXAMPLE 28 6- [1-Carbamoyl-5- (hept-1-ynyl) -5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one) -sp / ro-2'-oxirane

Elementary analysis: (raw formula:

molecular mass: 322.36)

C H N

% found 59.65 6.94 8.58

% calculated 59.62 6.88 8.69

EXAMPLE 29 6- [1-Chloroacetyl-5- [3- (3-phenylpropyl) oxiran-2-yl] -5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one] -sp / ro- 2'-oxirane Compound obtained according to the procedure described in Example 4, steps A to E, using in step A the appropriate acetylene derivative.

Elemental analysis: (gross formula: C2iH ₂₄ CIN0 ₆ molecular mass: 421, 88)

C H N Cl

% found 59.67 5.66 3.29 8.91% calculated 59.79 5.73 3.32 8.40

EXAMPLE 30 6- [1-Chloroacetyl-5- (1-chloroacetyl-carbamoyloxy-2-chloro-5-phenylpβntyl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2- one] -sp / ro-2'-oxlrane Compound obtained from the compound of Example 9, via treatment with an equivalent of 2-chloroacetyl isocyanate in dichloromethane.

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

Elementary analysis: (raw formula:

molecular mass: 577.85) CHN Cl

% found 49.27 4.67 4.79 18.49% calculated 49.89 4.71 4.85 18.41

EXAMPLE 31 1-Chloroacetylcarbamoyl-6-chloro-acerylcarbamoyloxy-5-heptyl-5-methyl-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 will have previously been reduced to 5-methyl-5-heptyl-dihydropyrano [3,2- d] oxazole-2,6-dione by catalytic hydroge¬ nation. Elemental analysis: (crude formula: C _& H∞CfeNaOβ molecular mass: 510.38)

C H N Cl

% found 46.83 5.70 7.92 14.00% calculated 47.07 5.73 8.23 13.89

EXAMPLE 32-1: 1-Chloroacόtylcarbamoyl-6-carbamoyl-oxy-5-heptyl-5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one

Compound obtained during purification by liquid chromatography (HPLC) on RP18 of the compound of Example 31. Elemental analysis: (crude formula:

molecular mass: 433.89)

C H N Cl

% found 49.76 6.50 9.62 8.77

% calculated 49.83 6.50 9.68 8.17

SUBSTITUTE SHEET (RULE 26) 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-carbamoyl-oxy-5- (hept-1-ynyl) -5- methyl-tetrahydropyrano [3 _t 2-d] oxazoμ2-one

Elementary analysis: (crude formula: CιβH ₂₄ CIN ₃ 0 ₈ molecular mass: 429.86)

C H N Cl

% found 50.66 5.70 9.63 8.10

% calculated 50.30 5.63 9.78 8.25

EXAMPLE 32-3: 1-Carbamoyl-6-chloroacόtylcarbamoyl-oxy-5- (hepM-ynyl) -5- methyl-tetrahydropyrano [3,2-d] oxazol-2-one

Elemental analysis: (gross formula: Cι ₈ H ₂₄ CIN ₃ 0 _B molecular mass: 429.86)

C H N Cl

% found 50.26 5.68 9.43 8.17% calculated 50.30 5.63 9.78 8.25

EXAMPLE 32-4: 1 -Carbamoy l-6-carbamoy loxy-5- (hept-1 -y ny l) -5-méthy l-tétra- hydropyrano [3,2-d] oxazol-2-one

Spectral characteristics:

¹ H NMR, (DMSO), δ (ppm): 7.52 (1H, s); 7.11 (1H, s); 6.5 (2H, s); 5.81 (1H, d); 4.6 (1H, t); 4.31 (1H, 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).

SUBSTITUTE SHEET (RULE 26 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 acetylene derivative.

EXAMPLE 33 1-Chloroacetylcarbamoyl-6-chloroacetylcarbamoyloxy-5- (5-phenylpent-1-ynyl) -5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one

Elementary analysis: (raw formula:

molecular mass: 554.39)

C H N Cl

% found 51.79 4.45 7.24 13.09

% calculated 52.00 4.55 7.58 12.79

EXAMPLE 34 1-Chloroacetylcarbamoyl-6-chloro-acetylcarbamoyloxy-5- (5-phenylpentyl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one

Elemental analysis: (crude formula: C ₂₄ H29CI ₂ N ₃ Oβ molecular mass: 558.42) CHN Cl% found 51.86 5.19 7.47 12.99

% calculated 51.62 5.23 7.52 12.70

EXAMPLE 35 1-Chloroacetylcarbamoyl-5- (hept-1-ynyl) -5-methyl-dihydro-pyrano [3,2-d] oxazole-2,6-dione

Compound obtained from the diastereoisomer A (5- (hept-1-ynyl) -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione) of step C of Example 1, that it is reacted with 2-chloroacetyl isocyanate instead of 2-chloroacetyl chloride according to the procedure described in step E of Example 4.

Elementary analysis: (gross formula: C ₁₇ H ₂ ιCIN ₂ 0 ₆ molecular mass: 384.82) CHN Cl % found 52.87 5.56 7.16 9.47

% calculated 53.06 5.50 7.28 9.21

EXAMPLE 36 1 -Chloroacόtylcarbamoyl-5- (5-methylhex-1-ynyl) -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Compound obtained according to the procedure described for Example 35, using in step A of Example 1, the appropriate acetylenic derivative.

Elemental analysis: (crude formula: Cι H ₂ ιCIN ₂ 0 ₆ molecular mass: 384.82) CHN Cl

% found 53.13 5.59 7.08 9.32% calculated 53.06 5.50 7.28 9.21

EXAMPLE 37 1 -Chloroacety lcarbamoyl-5- (5-methylhex-1-yl) -5-methyl I- dihydropyrano [3,2-d] oxazol-2,6-dione

Compound obtained via catalytic hydrogenation of the compound of Example 35. Elemental analysis: (crude formula:

molecular mass: 388.85) CHN Cl

% found 53.03 6.57 7.12 9.29

% calculated 52.51 6.48 7.20 9.12

EXAMPLE 38 1-Carbamoyl-5- (5-methylhexyl) -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Compound obtained during the purification of the compound of Example 37, by HPLC on RP 18.

Elemental analysis: (crude formula: C ₁₅ H ₂ 4N ₂ O ₅ molecular mass: 312.37) CHN

% found 58.10 7.84 8.86% calculated 57.68 7.74 8.97

SUBSTITUTE SHEET (RULE 26) EXAMPLE 39 1-Chloroacetylcarbamoyl-5-heptyl-5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Compound obtained according to the procedure of Example 35, by reacting in step A of Example 1, the lithian of furan on the octanal in tetrahydrofuran at -

78 ° C.

Elementary analysis: (crude formula: CiβH∞C Oβ molecular mass: 374.82)

C H N Cl

% found 51.35 6.17 7.40 9.47

% calculated 51.27 6.18 7.47 9.46

EXAMPLE 40: N- (1-Chloroacetyl-5-heptyl-5-methyl-2-oxo-ρerhydropyrano

[3,2-d] oxazol-6-yl) acetamide

Step A: N- (5-heptyl-5-methyl-2-oxo-perhydropyrano [3,2-d] oxazol-6-yl) acetamide

Compound obtained from 5-methyl-5-heptyl-dihydropyrano [3,2-d] oxazole-2,6-dione, itself obtained by catalytic hydrogenation (palladium on carbon, ethyl acetate, 1 atmosphere) by treatment with ammonium acetate (9 eq.) in the presence of sodium cyanoborohydride (20 eq.) in methanol at room temperature for one 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 silica (heptane / ethyl acetate, 1: 4), N- (5-heptyl-5-methyl-2-oxo-peιtιydropyrano [3,2-d] oxazol-6 is obtained -yl) acetamide used as such thereafter.

Step B: N- (1-Chloroacetyl-5-heptyl-5-methyl-2-oxo-perhydropyrano [3,2-d] oxazol-6-yl) acetamide

SUBSTITUTE SHEET (RULE 26) The compound obtained in step A is treated with 2-chloroacetyl chloride according to the procedure described described in step E of Example 4, to yield the expected product in the form of a white powder Spectral characteristics: NMR ¹ H (DMSO), δ (ppm): 8.5 (1H, s); 6.55 (1H, d); 6.15 (1H, d); 5.0 (1H, dd); 4.8 (2H, dd); 2.0 (3H, s); 1.9 (1H, m); 1.55 (1H, m); 1.45 (5H, m); 1.6-1.10 (10H, m); 0.85 (3H, t).

EXAMPLE 41 1-Chloroacetyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Compound obtained from 6-hydroxy-2H-pyran-3 (6H) -one, prepared according to M. P. Georgiadis et al., Org. Prβp. Proc. Int., (1992), 24 (1), 95-118) according to the procedure of Example 1, step C, then treatment of the crude product obtained, at room temperature, in acetone for 24 hours.

Elemental analysis: (crude formula: C ₈ H _θ CINθ5 molecular mass: 233.61) CHN Cl% found 41.48 3.78 6.30 15.13

% calculated 41.13 3.45 6.00 15.18

EXAMPLE 42 1-Chloroacetyl-5-heptyl-5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione 6- (0-acetyloxime)

Step A: 5- (hept-1-ynyl) -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione 6-oxime

To a solution of the diastereoisomer A of 5- (hept-1-ynyl) -5-methyl-dihydropyrano [3,2-d] oxazolθ-2,6-dione (1.08 g; 0.004 mol), obtained with 1 step C of Example 1, in methanol (35 ml), hydroxylamine hydrochloride (1.8 g; 0.0259 mol) and sodium acetate (3 g; 0.022 mol) are added. 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 taken up in the diethyl ether and the desired product is precipitated from hexane. A beige powder (700 mg) is obtained which is used as it is subsequently.

Step B: N- (5-heptyl-5-methyl-2-oxo-2,3a, 5,7a-tetrahydro-1 pyrano [3,2-d] oxazol-6-yl) acetamide

The compound obtained in step A (400 mg, 1.4 mol) in an acetic acid (12 ml) / acetic anhydride (40 ml) mixture is stirred in the presence of palladium on carbon (80 mg) under hydrogen atmosphere , at atmospheric pressure and ambient temperature for 14 hours. The reaction medium is then filtered through celite, azeotroped with toluene. A gummy residue is obtained which is crystallized from a diethyl ether / pentane mixture. 240 mg of a beige powder are then obtained which is used as it is subsequently. The filtrate mainly consists of 5-heptyl-5-methyl-dihydropyrano [3j2-d] oxazole-2,6-dione 6 (Oacetyloxime) which will be used for the preparation of the compound of Example 42.

Step C: 1-Chloroacetyl-5-hptptyl-5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione 6- (0-acetyloxime)

The compound obtained in step B is treated with 2-chloroacetyl chloride, in the presence of n-butyllrthium under the operating conditions described in step E of Example 4.

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

EXAMPLE 43 1-Chloroacόtyl-5-heptyl-5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione 6-oxime

Treatment with 2-chloroacetyl chloride (under the operating conditions described in step E of example 4) of the compound obtained in step A of example 42 leads to the expected product. Spectral characteristics: ¹ H NMR, (DMSO), δ (ppm): 11 (s, 1 H); 6.05 (d, 1H); 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).

EXAMPLE 44 6-Butyl-1-chloroacetyl-5-heptyl-5-methyl-6-hydroxy-tetra-hydropyrano [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 provides a crude product which is purified by chromatography on a silica column to obtain the expected product. Spectral characteristics: ¹ H NMR, DMSO, δ (ppm): 5.95 (1 H, d); 4.8 (2H, dd); 4.3 (1H, q); 3.55-3.45 (1H, d); 2.60-2.55 (2H, dd); 1.8-1.2 (19H, m); 0.9 (6H, t).

EXAMPLE 45 Chloroacetyl-5-hexyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Step A: 1- (2-furyl) heptan-1-ol

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., 105 ml of n-butyllithium (2.5 M) are added dropwise ) in hexane. Stirring is continued 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 again stirred for one hour at -78 ° C. The solution is then hydrolyzed with a saturated aqueous solution of sodium chloride and then extracted with pentane. The organic phases collected are dried over magnesium sulphate then filtered and concentrated. An orange oil is obtained (38.6 g) corresponding to the expected product, and is used as such subsequently.

Step B: 1-Chloroacetyl-5-hexyl-dihydropyrano [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 to result in a mixture of two isomers.

SUBSTITUTE SHEET (RULE 26) Diastereoisomer A is isolated by chromatography on silica. Rf = 0.39 (cyclohexane / ethyl acetate, 80:20). Spectral characteristics:

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

Example 46: 1-Chloroacetyl-5-hexyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Second diastereoisomer obtained during the synthesis of the compound of Example 45. Rf = 0.33 (eluent: cyclohexane / ethyl acetate, 80:20). Spectral characteristics:

¹ H NMR, (DMSO), δ (ppm): 5.98 (d, 1H); 4.82-4.72 (dd, 2H); 4.78 (m, 1H); 4.2 (dd, 1H); 3.0 (dd, 1H); 2.85 (dd, 1H); 1.7 (m, 1H); 1.55 (m, 1H); 1.45-1.15 (m, 8H); 0.83 (t, 3H).

Example 47: (3aS, 5/7, 7aS) -1-Chloroacetyl-5-trityloxymethyl-dihydropyrano

[3,2-d] oxazole-2,6-dione

Compound obtained by proceeding according to the procedure described in steps B and C of Example 1, starting from (1 fl) -1- (2-furyl) -2-trityloxyethanol (described in MP Qeorgiadis et al., Pol. J. Chβm., (1990), 64, 823-826). Spectral characteristics:

¹ H NMR, (DMSO), δ (ppm): 7.5-7.2 (15H, m); 6.4 (1H, d); 5.05 (1H, m); 4.8 (2H, AB); 4.4 (1H, t); 3.35 (2H, d); 3.2 (1H, d); 3.0 (1H, d).

SUBSTITUTE SHEET (RULE 26) Exemole 48: 2- (1-Chloroacetyl-2,6-dioxo-dihydropyrano [3,2-d] oxazol-5-yl) ethyl acetate

Compound obtained by proceeding according to the procedure described in step C of Example 1, starting from (6-hydroxy-3-oxo-3,6-dihydro [2 τ] pyran-2-yl) acetate ethyl (prepared according to Sato et al., J. Org. Chem., (1989), 54, 2085-2091).

Example 49: Benzyl - [(1-chloroacetyl-5-heptyl-6-hydroxy-5-methyl-2-oxo-tetrahydropyrano [3,2-d] oxazol-6-yl) methyl] methylsulfonium

Compound obtained according to the procedure described in Example 10, by reacting 6- (5-heptyl-5-methyMetrahydropyrano [3,2-d] oxazol-2-one] sp / ro-2'-oxirane with sodium methane dithiolate in dimethylformamide, 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-chloroacetylcarbamoyloxy-5-heptyl-5-methyl-2-oxo-tetrahydropyrano [3,2-d] oxazol-6-yl) methyl] methylsulfonium

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 - [(1-Chloroacetyl-5-heptyl-6-hydroxy-5-methyl-2-oxo-tetrahydropyrano [3,2-d] oxazol-6-yl) methyl] -1, 3-dihydro- benzo [c] thienylium

The 6- (5-hθptyl-5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one] sp / ro-2'-oxirane obtained via catalytic hydrogenation of the compound obtained in step B of the example 4 is treated with (2-mercaptobenzyl) methanol, in the presence of sodium methylate in methanol, the benzyl alcohol function is then treated with methanesulfonyl chloride, in the presence of triethylamine in dichloromethane. Cyclization to dihydrobenzo [c] thiophene is finally obtained by heating to 30 ° C in dichloromethane. The compound thus obtained is then chloroacetyl according to the procedure described in step E of Example 4.

Example 52: 1-Chloroacetyl-5-hexyl-7a-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Compound obtained according to the procedure described in Example 45 from 4-methyl-2-bromofuran (prepared according to M.E. Maier et al., Tel Lett., (1991), 32, 53-56) and heptanal.

Example 53: 1-Chloroacetyl-5-hexyl-7-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione Compound obtained by proceeding according to the procedure described in Example 41 from 2-hexyl -6-hydroxy-4-methyl-6H-pyran-3-one (obtained via oxidative rearrangement of 1- [2- (3-methylfuryl)] hexan-1-ol prepared according to Sato et al., J. Org. Chem ., (1989), 54, 2085-2091).

Example ^p 54: 1-Chloroacetyl-7-methoxy-5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Proceeding as described for Example 53, starting from 6-hydroxy-4-methoxy-2-methyl-6W-pyrane-3-one (obtained via oxidative rearrangement of prepared 3-methoxy-furan-2-yl-methanol according to PA Weeks et al., J. Org. Chem., (1980), 45, 1109).

Example 55: 3a-Benzyloxymethyl-1-chloroacetyl-dihydropyrano [3,2-d] oxazole-2,6-dione

By proceeding as described in Example 1, steps B and C, starting from 2-benzyloxymethyl-5-hydroxymόthylfurane (prepared according to O. Achmatowicz et al., Tθtrahθdron, (1982), 38, 3507-3513) the title product is obtained.

SUBSTITUTE SHEET (RULE 26) By proceeding in a similar manner to the examples previously described, the following compounds were obtained:

Example 56: 3a-Benzyloxymethyl-1-chloroacetylcarbamoyl-5,7a-dimethyl-5-heptyl-dihydropyrano [3,2-d] oxazole-2,6-dione

Example 57: 6- [1-Chloroacetyl-3a-dimethylaminoethyl-7-methyl-5,5-diphenyl-tetrahydropyrano [3,2-d] oxazol-2-one] -sp / ro-2'-oxirane

Example 58: 6-Acetylamnno-1-chloroacetyl-5-heptyl-perhydropyrano [3,2-d] oxazol-2-one

Example 59: 6-Acetylamino-1-chloroacetyl-5-heptyl-7a-methylperhydro-pyrano [3,2-d] oxazol-2-one

Example 60 6-Benzyloxy-3a-benzyloxymethyl-1-chloroacetylcarbamoyl-5-heptyl-5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one

Example 61: 1- (2-Chloropropanoyl) -5-heptyl-dihydro [3,2-d] oxazole-2,6-dione

Example 62: 6-Butyl-1-chloroacetylcarbamoyl-5- (2-chloro-1 -chloroacety I- carbamoyloxyheptyl) -5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one

Example 63: 1-Chloroacetyl-5,7-dimόthyl-6-methylamino-5- (3-pentyl-oxiran-2-yl) -tetrahydropyrano [3,2-d] oxazol-2-one

Example 64: 1-Chloroacetylcarbamoyloxy-6-diethylamino-5-heptyl-tόtra-hydro-pyrano [3,2-d] oxazol-2-one

Example ^p 65: 6-Benzylydene-5- (3-chloroacetylcarbamoyloxypropyl) -1 ~ cinnamoyl-5-methyl-dihydropyrano [3,2-d] oxazol-2-one

SUBSTITUTE SHEET (RULE 26) PHARMACOLOGICAL STUDY

EXAMPLE A Study of the anti-proliferative activity of the compounds of the invention

Three cell lines were used: - 1 murine leukemia, L1210, - 1 human squamous cell carcinoma, A431,

- 1 primary culture of pig aorta endothelial cells, CEAP.

The cells are cultured in complete RPMI 1640 culture medium containing 10% of fetal calf serum, 2 mM of glutamine, 50 units / ml of penicillin, 50 μg / ml of streptomycin and 10 mM of HEPES (pH = 7 , 4).

The cells are distributed in microplates and exposed to cytotoxic compounds.

The cells are then incubated for two days (L1210), 3 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 WG, Gazdar AF, Minna JD and Mitchell JR, Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing, Cancer Res., 47, 936-942, (1987)).

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

EXAMPLE B Inhibition of the neovascularization of the chorioallantoic membrane of a chicken embryo

This test is carried out with chicken embryos as described above (Crum R., Szabo S. and Folkman J., Science, (1985), 230, 1375-1378). Fertilized eggs (D0) are incubated at 37 ° C. An air pocket is created by taking 1 ml of albumin (J3), then a window is cut in the shell (J4) and the yolk membrane is removed to release the chorio-allantoic membrane (MCA). The products to be tested are dissolved in ethanol and deposited on methylcellulose discs which are dried and deposited on the MCA on day 6. Between 8 and 16 eggs are used per group. The area around the disc is then examined 48 hours later. Eggs with an avascular zone greater than 4 mm in diameter are counted and the results are expressed as a percentage of eggs with an avascular zone. The results obtained for each of the compounds of the invention are indicated in Table 1 below:

- Table 1 -

Inhibition of neovascularization of the chorioallantoid membrane of chicken embryos

Composed of 8% egg with an avascular zone

Example 1 70 ± 10

Example 9 89 ± 7

Example 11-1 87 ± 6

Example 15 65 ± 15

Example 16 85 ± 5

Example 17 73 ± 8

Example 21 71 ± 8

Example 26 71 ± 1

Example 31 86 ± 4

Example 32-1 76 ± 13

Example 33 90 ± 4

Example 34 75 ± 15 EXAMPLE C: Antitumor activity

The antitumor activity of the compounds of the invention was studied according to the protocol described by R.l. Geran et al., Cancer Chemiottierapy Reports, (1972), Part 3, pages 3 ff.

Mice were randomly assigned to treated groups (11 mice / group) and to a control group of 40 mice.

Tumor fragments were implanted on day 0 (subcutaneous implant). The test compounds were administered for 12 days (day 1 to day 12) i.p.

The average tumor weight was determined on day 13 after implantation. The percentage of inhibition was calculated according to the formula:

% Inhibition = 100 - mean tumor ^weight (treatment group) mean tumor weight (control group)

By way of example, the compound of Example 31 showed an inhibition of 79% at the dose of 120 mg / kg.

EXAMPLE D: PHARMACEUTICAL COMPOSITION: TABLETS

Preparation formula for 1000 tablets dosed at 50 mg.

Compound of example 31 50 g

Wheat starch 15 g

Corn starch 15 g Lactose 65 g

Magnesium stearate 2 g

Silica 1 g

Hydroxypropylcellulose 2 g

SUBSTITUTE SHEET (RULE 26)

Claims

1. Compounds of general formula (I):

in which :

"Ri is chosen from the radical R and the radical -NH-CO-R,

R is chosen from the amino radical, an alkylamino, dialkylamino, alkyl, alkenyl, aikoxy, aryl, arylalkyl, heteroaryl, heteroaryialkyl, aryloxy and heteroaryloxy radical,

R ₂ is chosen from hydrogen and an alkyl radical,

• R ₃ is chosen from hydrogen, an alkyl radical, the hydroxy radical, an aikoxy radical, an aryl radical, an arylalkyl radical, a - (CH ₂ ) _n -ORβ radical, and a - (CH ₂ ) _n radical -NR _β R9,

• R ₄ 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 heteroaryialkyl radical or else forms with Y a bond,

SUBSTITUTE SHEET (RULE 26) • R ₇ is chosen from hydrogen, an alkyl radical, an arylalkyl radical, a - (CH ₂ ) _n -OR ₈ radical, a - (CH ₂ ) _n -0-CO-R ₈ radical and a - ( CH ₂ ) _n -NR ₈ R _9>

• R ₈ and R ", which are identical or different, are chosen, independently of one another, 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, the hydroxy radical, an aikoxy radical, the amino radical, an alkylamino, dialkylamino radical, the radical -O-CO-RS and the radical -NH-CO-RS, where R'i the same definition as Ri defined above and Y represents hydrogen, or,

* X represents hydrogen and Y forms with R ₄ or R ₅ a bond, or else,

"X and Y together form a methylene group, a group = CH-alkyl, a ≈CH-aryl group or a group = CH-arylalkyl, or else,

* X and Y together form an oxo group, or,

"X and Y together form an oxirane ring, with the carbon atom that carries them, or,

* X and Y together form the hydroxyimino radical or a ≈NO-CO-R'i radical, where R'i has the same definition as Ri previously defined, or else, "X is chosen from an alkyl radical, a radical arylalkyl and a radical

R. -CH-S ^, and Y is chosen from hydrogen, hydroxy group and

Rb radical O-CO-NH-CO-R 'where R' has the same definition as R previously defined, or forms with R or R5 a bond,

• R _a and R _b , which are identical or different, are chosen, independently of one another, from an alkyl radical, an aryl radical, an arylalkyl radical, a heteroaryl radical and a heteroaryialkyl radical, or alternatively, 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 -1 -yle, perhydrobenzo [c] thien-2- yl and perhydrothienyl,

Being heard that :

the term "alkenyl" denotes a radical containing from 2 to 10 carbon atoms in a straight or branched chain, optionally substituted, and comprising an unsaturation in the form of double bond,

the term "alkynyia" denotes a radical containing from 2 to 10 carbon atoms in a straight or branched chain, optionally substituted, and comprising an unsaturation in the form of triple bond,

the term "heteroaryl" included in the heteroaryl, heteroaryloxy and heteroaryialkyl radicals denotes an optionally substituted radical chosen from furyl, thienyl, thiazolyl, imidazolyl, thiadiazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, indolyl and isoindolyl

and

SUBSTITUTE SHEET (RULE 26) - The term "optionally substituted" means that the radicals thus qualified may optionally be substituted by one or more chemical entities chosen from:

- hydroxy, - 0-CO-R'ι, where R'i has the same definition as Ri previously defined,

- aikoxy,

- alkyl, alkenyl, alkynyia,

- epoxy,

- alkylthio, - halogen, chosen from fluorine, chlorine, bromine and iodine,

- trihaiogenomethyl,

- nitro, amino, alkylamino and dialkylamino,

- carboxy,

- alkoxycarbonyl, - alkylcarbonyl,

- alkoxycarbonylalkyle,

- carboxyalkyl,

- aryle, 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 as a mixture, their optional addition salts with an acid, which are pharmaceutically acceptable, as well as their possible S-oxides, N-oxides or quaternary ammonium salts.

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

SUBSTITUTE SHEET (RULE 26)

4. Compounds according to claim 1, for which Y represents hydrogen and X represents a radical -0-CO-R'ι, where R'i is as defined in claim 1, their possible geometric isomers and optical isomers, in pure form or in the form of a mixture, their optional pharmaceutically acceptable acid addition salts, as well as their possible S-oxides, N-oxides or quaternary ammonium salts.

5. A compound according to claim 1 which is 1-chioroacetyl-5-heptyl-dihydro-pyrano [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-chloroacetyl-carbamoyl-6-chloroacetylcarbamoyloxy-5- (5-phenylpent-1-ynyl) -5-methyl-tetra-hydropyrano [3,2-d] oxazol- 2-one, and its optical isomers in pure form or as a mixture.

7. A compound according to claim 1 which is 1-chloroacetyl-carbamoyl-6-chloroacetylcarbamoyloxy-5-hθptyl-5-methyl-tetrahydropyrano [3,2-d] oxazol-2-one, and its optical isomers in the form pure or as a mixture.

8. A compound according to claim 1 which is 1-chloroacetyl-5- (1-hydroxy-2-chloro-5-phenylpentyl) -5-methyl-tetrahydropyrano [3,2-d] oxazol-2-oneJ-sp / ro-2'- oxirane, and its optical isomers in pure form or as a mixture.

9. A process for preparing 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):

where R ₂ , R ₃ , R ₅ , R _β and R ₇ are as defined in claim 1, in aprotic polar solvent, at an appropriate temperature, chosen from a range from -100 ° C to 30 ° C, in order to produce furylcarbinol of formula (IV):

in which R ₂ , R ₃ , R ₅ , Rβ and R ₇ are as defined above,

which, subject to oxidation, in the presence of an acid, in an appropriate solvent, at a temperature between 0 ° C and 22 ° C, is rearranged into pyranone of formula (V):

in which R ₂ , R ₃ , R ₅ , Rβ and R ₇ are as defined above,

in which R ₂ , R _{3 (} Rs, Rβ and R ₇ are as defined above, special case of the compounds of formula (I) according to claim 1 where Ri represents the radical -CH ₂ -CI, X and Y together form the oxo group and R ₄ represents hydrogen,

compound of formula _(a) which can be cleaved under the action of an alcohol, or a weak base, a compound of formula (VI):

where R ₂ , R ₃ , R ₅ , Rβ and R ₇ are as defined above,

whose oxo group carried by the carbon atom 6 is subjected to various conventional reactions, so as to lead to the compound of formula (l _d ) 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 else by the action of an isocyanate of formula R-CO-NCO, where R is as defined in claim 1, in order d '' respectively obtain the compounds of formulas (l _t >) and

in which R ₂ , R ₃ , Rβ, Rβ and R ₇ are as defined above, and FU, X and Y are as defined in claim 1,

all of the compounds of formula (lt _> ) and (l _c ) forming all of the compounds of formula (I) which are purified if necessary by a conventional purification technique, from which, if desired, they are separated geometric isomers and optical isomers by a conventional separation technique which is converted, where appropriate, into their N-oxides, S-oxides, their pharmaceutically acceptable acid addition salts or their salts of 'quaternary ammonium.

10. Pharmaceutical compositions containing as active ingredient 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.

SUBSTITUTE SHEET (RULE 26)

11. Pharmaceutical compositions according to claim 10 exerting an inhibitory activity of angiogenesis, and useful in the treatment of conditions due to or connected with disorders of angiogenesis.