EP1173455A2

EP1173455A2 - Novel ribose-substituted aromatic amides, method for the production and use thereof as medicaments

Info

Publication number: EP1173455A2
Application number: EP00920823A
Authority: EP
Inventors: Jacques Demassey; Michel Klich; Branislav Musicki
Original assignee: Aventis Pharma SA
Current assignee: Novexel SA
Priority date: 1999-04-19
Filing date: 2000-04-18
Publication date: 2002-01-23
Also published as: PL354192A1; CN1357001A; EA004304B1; AP2001002312A0; FR2792320B1; KR20020008155A; HUP0200778A2; JP2002542253A; ID30562A; AU4125600A; ZA200108627B; UA72919C2; FR2792320A1; EA200101100A1; SK14842001A3; HK1046690A1; TR200103009T2; WO2000063222A3; HK1046690B; NO20015058D0

Abstract

Compounds of formula (I); wherein R1 = alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or optionally substituted, optionally interrupted O-alkynyl; R2 = hydrogen or halogen; R3 = hydrogen, alkyl or halogen; R4= NHR' or NHOR'', R' or R'' are identical or different and represent hydrogen, alkyl, alkenyl or alkynyl, aryl; R5= hydrogen or O-alkyl; R6= alkyl or CH2-O-alkyl; R7= hydrogen or alkyl or R6 et R7 form a cycle together with the carbon carrying them in addition to the addition salts thereof with bases. The compounds of formula (I) have antibiotic properties.

Description

New aromatic ribide substituted amides, process for their preparation and their use as medicaments

The present invention relates to new aromatic amides substituted with a ribose, their preparation process and their use as medicaments.

The subject of the invention is the compounds of formula (I):

in which

R1 represents an alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-linear or branched or cyclic O-alkynyl radical containing up to 8 carbon atoms optionally substituted by one or more halogen atoms, optionally interrupted by a d atom oxygen, sulfur or nitrogen, an aryl or aralkyl radical containing up to 18 optionally substituted carbon atoms, an heterocyclic radical, aromatic or not, mono or polycyclic optionally substituted, an NH ₂ , NHalci or NHalc ₂ , NHalc radical ₃ or NH0alk ₄ , alki, alk ₂ , alk ₃ and alk representing an alkyl radical containing up to 8 carbon atoms,

R ₂ represents a hydrogen atom or a halogen atom, R ₃ represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or a halogen atom,

R ₄ represents an NHR 'or NHOR''radical in which R' or R '', identical or different, represent a hydrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 8 carbon atoms, an aryl radical containing up to 14 optionally substituted carbon atoms,

R ₅ represents a hydrogen atom or an O-alkyl radical containing up to 8 carbon atoms, R ₆ an alkyl or CH ₂ -0 -alkyl radical, in which alkyl represents an alkyl radical containing up to 8 carbon atoms,

R ₇ represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms or else R ₆ and R ₇ form together with the carbon which carries them a ring as well as their addition salts with bases.

Examples of bases that may be mentioned are the salts formed with the amines such as arginine, lysine, Na ⁺ , K ⁺ , NH ₃ ⁺ , N (alk) ₃ ⁺ alk ₃ ions representing an alkyl radical containing up to 8 carbon atoms.

In the definition of substituents:

the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl radical,

- the halogen is preferably fluorine or chlorine, or bromine, - the aryl radical is preferably the phenyl radical. A more particular subject of the invention is the compounds of formula (I) in which R 1 represents an alkyl radical containing up to 4 carbon atoms, for example a radical

the compounds of formula (I) in which R 1 represents a benzoyl radical, the compounds of formula (I) in which R ₂ represents a hydrogen atom, the compounds of formula (I) in which R ₃ represents a methyl radical, the compounds of formula (I) in which R ₅ is an OCH ₃ radical, the compounds of formula (I) in which R ₆ and R ₇ represent a methyl radical or an ethyl radical as well as those in which R ₆ and R ₇ form with the carbons which carry them a cyclopentyl radical.

Among the preferred compounds of the invention, one can cite the compounds of formula (I) in which R ₄ represents an NH-O-CH ₂ -C≡CH radical.

The subject of the invention is very particularly the compounds the preparation of which is given below in the experimental part and very particularly the product of Examples 10 and 11. The products of general formula (I) have a very good antibiotic activity on anaerobic gram bacteria such as staphylococci, streptococci, pneumococci, enterococci, listeria. The compounds of the invention can therefore be used as medicaments in the treatment of infections with sensitive germs and, in particular, in that of staphylococcal diseases, such as staphylococcal septicemia, malignant staphylococcal disease of the face or skin, pyoderma, septic wounds or suppurative, boils, carbuncles, phlegmons, erysipelas and acne, staphylococcal diseases such as acute primary or post-influenza angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlet fever , pneumococcal diseases such as pneumonia, bronchitis and diphtheria. The products of the present invention are also active against infections caused by germs such as Haemophilus influenzae.

A subject of the invention is therefore the compounds of formula (I) as well as their pharmaceutically acceptable salts as medicaments.

A more particular subject of the invention is, as medicaments, the compounds indicated above as preferred compounds. A subject of the invention is also the pharmaceutical compositions containing as active principle at least one of the medicaments defined above.

These compositions can be administered by the buccal, rectal, parenteral route or by the local route by topical application to the skin and the mucous membranes, but the preferred route of administration is the buccal or injectable route. They can be solid or liquid and come in the pharmaceutical forms commonly used in medicine. human cine, such as for example simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

These compositions can also be in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example sterile non-hydrogenated water.

The dose administered is variable depending on the condition treated, the subject in question, the route of administration and the product considered. It may, for example, be between 50 mg and 3000 mg per day by oral or injectable route, in adults for the preferred products.

The subject of the invention is a process for preparing the compounds of formula (I) characterized in that a compound of formula (II) is subjected:

O

II to the action of a compound of formula ^R ι ^{c Hal} in which R retains its previous meaning and Hal represents a halogen atom to obtain the compound of formula (III)

that we submit to the action of a compound of formula

R ₄ H (IV)

to get the compound of formula

A subject of the invention is also, as new chemicals, the compounds of formula (II) and (III). In a preferred embodiment, Hal is a chlorine atom.

The compounds of formula (II) used as starting materials for the process of the invention can be prepared as indicated below in the experimental part. The preparation of the compounds of formula (II) described in the experimental part can be schematized as follows:

The invention also relates to a process characterized in that a compound of formula (V) is subjected:

in which the substituents retain their meaning previous and OM represents a blocked hydroxyl radical, to the action of a compound of formula RiCOHal in which Ri retains its previous meaning and Hal represents a halogen atom, then to the action of a function-releasing agent OH to obtain the corresponding compound of formula (I):

The products of formula (V) used as starting materials are new products and are in themselves an object of the invention. The compounds of formula (V) can be prepared according to the process indicated in the experimental part. The experimental part can be schematized as follows. Preparation 1: 4,7-dihydroxy-8-methyl-3- (phenylazo) -2H-1- benzopyran-2-one Stage A: C ₆ H ₅ N ⁺ ≡N, C1 ^~

30.86 ml of aniline are introduced at 10 ° C. into 138 ml of a 36% hydrochloric acid solution. A solution containing 23.32 g of sodium nitrite and 123 ml of water is added while maintaining the temperature between 0 and 5 ° C. A solution is obtained which is maintained at 5 ° C for 45 minutes. A product is obtained which is used as is below. Stage B: 4, 7-dihydroxy-8-methyl-3- (phenylazo) -2H-1- benzopyran-2-one

33.75 g of 4,7-dihydro-8-methyl-2H-1-benzopyran-2-one are introduced into 1.1 l of ethanol. 138.3 g of sodium acetate are added and 150 ml of product prepared in stage A are added. The reaction mixture is stirred for 30 minutes and 460 ml of water are added. We keep under agitation- tion for 1 hour. The product obtained is rinsed with water or methyl cyanide and with ether. Dried and obtained 87.34 g of the desired product.

Preparation 2: 2, 2, 3-carbonate cyclic and 1- (2,2,2-trichloroethanimidate) of 6-deoxy-5-C-methyl-4-0-methyl-L-lyxo-hexopy-ranose

Stage A: 2,3-cyclic 6-deoxy-5-C-methyl-4-0-methyl-1-L-lyxo-hexopyranose carbonate

50 g of 6-deoxy-5-C-methyl-4-0-methyl-L-lyxo-hexopyranose are introduced into 2 l of 1,2-dichloro-ethane. 44.3 g of carbonyl diimidazole are added. The mixture is brought to reflux for 3 h 30 min. It is allowed to return to room temperature. Concentrate and obtain 120 g of product which is chromatographed on silica eluting with a mixture of methylene chloride acetone 9-1. 23.19 g of sought product is thus obtained.

Stage B: cyclic 2,3-carbonate and 1- (2,2,2-trichloro-etanimidate) of 6-deoxy-5-C-methyl-4-0-methyl-L-lyxo-hexopyranose Introduced 276 mg of cesium carbonate, 18.17 g of the product prepared in stage A and 16 ml of trichloromethane cyanide in 250 ml of methylene chloride. The reaction mixture is kept under stirring for 3 hours. 7 ml of trichloromethane cyanide are added. Stirring is continued for 1 hour and the product obtained is brought to dryness, eluting with a cyclohexane ethyl acetate mixture (5-5). 27.01 g of sought product are thus obtained. EXAMPLE 1 Cyclopropyl-carbamic acid 3 ′ -ester of N- [7- [(6-deoxy-5-C-methyl-4-0-methyl-. Alpha. -L-lyxo-hexopyra-nosyl) oxy] - 4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] - cyclopropanamide

Stage A: 7- [(2,3-0-carbonyl-6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy]] -4-hydroxy-8 -methyl-3- (phenylazo) -2H-1-benzopyran-2-one

36.7 g of product of preparation 1 and 25 g of product of preparation 2 are introduced into 500 ml of methylene chloride. 1.2 ml of BF ₃ and Et ₂ 0 are added. The mixture is stirred for 20 hours at 20 ° C. 100 ml of water are added, the mixture is stirred, filtered and decanted. The precipitate is washed with methylene chloride, decanting, washing the organic phases with water, bringing them together, drying them and concentrating. 500 ml of ethyl ether are added. The mixture is stirred for 1 hour at 20 ° C and 15 minutes at 0 ° C. It is filtered, rinsed and washed with ethyl ether. The desired product is thus obtained 30 g (71%).

Stage B: 3-amino-7- [(2, 3 -0-carbonyl-6-deoxy-5-C-methyl-4-0- methyl- .alpha. -L-lyxo-hexopyranosyl) oxy]] -4 -hydroxy-8-methyl- 2H-1-benzopyran-2-one

30 ml of water, 1.8 g of sodium acetate and 1.7 g of dithionite are added to a suspension containing 1.5 g of product from the previous stage and 15 ml of ethanol. The mixture is brought to reflux in 30 minutes. The reflux is maintained for 10 minutes. We filter. It is brought back to 20 ° C., cooled to 0 ° C. We drain, paste with ethyl ether, spin and dry. This gives the desired product (858 mg).

Stage C: N- [7- [(2,3-0-carbonyl-6-deoxy-5-C-methyl-4-0- methyl- .alpha. -L-lyxo-hexopyranosyl) oxy]] -4- hydroxy-8-methyl- 2-oxo-2H-1-benzopyran-3 -yl] -cyclopropanecarboxamide

20 ml of ethyl acetate are added to 1 g of the product from the preceding stage. We grind with a spatula. 250 mg of pyridine are added. 256 mg of cyclopropane carboxylic acid chloride are added. The mixture is stirred for 1 hour 30 minutes at 20 ° C. Diluted with 100 ml of ethyl acetate and 50 ml of water. Decanted, washed with sodium hydrogen carbonate, water, and hydrochloric acid. It is dried, filtered and concentrated. The product obtained is chromatographed on silica eluting with a hexane / ethyl acetate mixture (1-1). The desired product is thus obtained. Stage D: Cyclopropyl-carbamic acid 3 ′ -N- ester [7 - [(6-deoxy-5-C-methyl-4-0-methyl-. Alpha. -L-lyxo-hexopyranosyl) oxy] -4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -cyclopro- panamide

82 μl of cyclopropylamine and 283 μl of 1,8-diazabicyclo [5.4.0] undec-7-ene are added to a solution containing 453 mg of product from the previous stage and 10 ml of DMF. The mixture is stirred for 20 hours at 20 ° C. Pour onto a dilute monosodium phosphate solution. Extracted with ethyl acetate, washed with water, dried, filtered and concentrated. We 563 mg of product is obtained which is chromatographed eluting with the heptane / ethyl acetate mixture 30-70. Eluted with methanol, 312 mg of product is obtained which is impasted in an ethyl acetate / methanol 8-2 mixture. We wring. Concentrate and obtain 113 mg of the desired product. Rf = 0.18 heptane / ethyl acetate 30-70.

EXAMPLE 2 Acid (1-methylethoxy) -carbamic 3 '-N- ester [7- [(6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy ] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] - cyclopropane-carboxamide

102 mg of sodium hydride are added to a suspension containing 237 mg of isopyloxyamine hydrochloride and 7.5 ml of DMF. The mixture is stirred for 1 hour at 20 ° C. 0.25 ml of triethylamine is added and the product prepared in stage C of Example 1. The mixture is brought to 50 ° C. for 3 hours, 150 mg of DMAP are added and the mixture is kept overnight at 50 ° C. 150 mg of DMAP and 132 mg of isopyloxyamine hydrochloride are added.

The mixture is stirred for 20 hours at 50 ° C. It is brought to 20 ° C. Poured onto a normal solution of ice-cold hydrochloric acid, extracted with ethyl acetate, washed with water, dried, filtered and concentrated. 253 mg of product is obtained which is chromatographed on silica eluting with a heptane / ethyl acetate mixture 3-7. 48 mg of sought product is obtained, rf = 0.15. EXAMPLE 3 (2-Propynyloxy) -carbamic acid 3 '-N- [7- [(6-deoxy-5-C-methyl-4-0-methyl-. Alpha. -L-lyxo-hexopyranosyl) oxy ester ] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] - cyclopropane-carboxamide

1.0 ml of solution of LiC10 ₄ in Et ₂ 0 3 molar are added to a suspension containing 302 mg of the product prepared in stage C of Example 1 and 5 ml of ethyl ether. The mixture is triturated. Place under ultrasound for 15 minutes. Stirring is continued for 5 hours, 15 ml of LiCl0 ₄ / Et ₂ 0 solution is added. The mixture is stirred for 16 hours at 20 ° C., diluted with ethyl acetate and washed with water. It is dried, filtered and concentrated. 365 mg of product are obtained which is chromatographed on silica eluent hexane / ethyl acetate (4-6) then with a methanol / ethyl acetate mixture 40-60. 36 mg of sought product is obtained. By operating as above, the following products were obtained:

- (1-Methylethoxy) -carbamic acid 3 '-N- ester [7 - [(6-deoxy-5-C-methyl-4-0-methyl-. Alpha. -L-lyxo-hexopyranosyl) oxy] - 4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -benzeneacetamide

- 3 'ethoxy-carbamic acid -N- ester [7- [(6-deoxy-5-C- methyl-4-0-methyl-. Alpha. -L-lyxo-hexopyranosyl) oxy] -4- hydroxy- 8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -benzeneacetamide - (1R-trans) Ethoxy-carbamic acid 3 '-ester of N- [7 - [(6-deoxy -5-C- methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2,2- dimethyl- 3-ethenyl-cyclopropanamide

- Cyclopropyl-carbamic acid 3'-ester of N- [7- [(6-deoxy-5- C-methyl-4-O-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4- hydroxy- 8-methyl-2-oxo-2H-1-benzopyran-3-yl] -benzeneeacetamide

- Cyclopropyl-carbamic acid 3 '- N- [7- [(6-deoxy-5- C-methyl-4-O-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4- hydroxy- ester 8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -benzenepropanamide

- (1-methylethoxy) -carbamic acid 3'-ester of N- [7 - [(6-deoxy-5-C-methyl-4-0-methyl-. Alpha. -L-lyxo-hexopyranosyl) oxy] - 4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] - benzenepro-panamide - Butoxycarbamic acid 3 '-ester of N- [7- [(6-deoxy-5-C - methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -2 -methyl- propanamide

- 3'-propoxy-carbamic acid -N- ester [7- [(6-deoxy-5-C- methyl-4-O-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4- hydroxy- 8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -2-methyl-propanamide

- Cyclopropyl-carbamic acid 3 '- N- [7- [(6-deoxy-5- C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4- hydroxy- ester 8-meythyl-2-oxo-2H-1-benzopyran-3-yl] - cyclobutanamide.

Preparation 3: 3-amino-7- [[6-deoxy-5-C-methyl-4-0-methyl-3- 0- [[(2-propynyloxy) amino] carbonyl] -2-0- [(tetrahydro -2H-pyran- 2-yl) oxy] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy-8- methyl-2H-1-benzopyran-2-one

Stage A: 7- [[6-deoxy-5-C-methyl-4-0-methyl-2-0- [(tetrahydro- 2H-pyran-2-yl) oxy] -3-0 [(triethylsily) oxy ] - .alpha. -L-lyxohexopyrano-syl] oxy] -4-hydroxy-8-methyl-2H-1-benzopyran-2-one It is subjected to hydrogenation under reduced pressure in the presence of palladium on carbon 28.0 g of product P prepared below. The palladium is filtered and rinsed with THF. Concentration is carried out under reduced pressure and 32.48 g of product are obtained which is purified on silica eluting with hexane / ethyl acetate 6-4.

Stage B: 7- [[6-deoxy-5-C-methyl-4-0-methyl-2-0- [(tetrahydro- 2H-pyran-2-yl) oxy] -3-0 [(triethylsily) oxy ] - .alpha. -L-lyxo- hexopyrano-syl] oxy] -4-hydroxy-8-methyl-3- (phenylazo) 2H-1- benzopyran-2-one

To 143 ml of normal hydrochloric acid solution at 0 ° C., 3.54 g of aniline are added. Stirring is continued at 0 ° C for 15 minutes, a solution of 2.9 g of sodium nitrite in 30 cm ³ of water is added. A solution of 14.39 g of sodium acetate in 150 ml of water is added. Stirring is continued for 15 minutes, a solution containing the product of the preceding stage is added in 150 ml of ethanol. Stirring is continued for 15 min at 0 ° C., 300 ml of AcOEt are added. Decanted, washed with sodium acid phosphate, dried and concentrated. 34 g of product are obtained, which product is purified by chromatography on silica eluting with hexane, then with hexane / ethyl acetate mixture 60-40. 17.55 g of product are obtained. Stage C: 7- [[6-deoxy-5-C-methyl-4-0-methyl-2-0- [(tetrahydro-2H-pyran-2-yl) oxy] -. alpha. -L-lyxo-hexopyranosyl] oxy] -4- 8-hydroxy-methyl-3- (phenylazo) -2H-1-benzopyran-2-one

57.5 ml of Bu ₄ NF molar solution in THF are added to a solution containing the product prepared in the preceding stage in 400 ml of THF. Stirring is continued at 0 ° C for 5 hours. Washed with saturated NaH ₂ P0 _{4 solution} , decanted, concentrated and dried. 34 g of product are obtained which is purified by chromatography on silica eluting with hexane 60 AcOEt40. 17.55 g of product are obtained research .

Stage D: 7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2-propanyyloxy) -amino] carbonyl] -2-0- [(tetrahydro- 2H-pyran-2-yl) oxy] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy-8 methyl -3- (phenylazo) -2H-1-benzopyran-2-one a) Dissolved at 0 ° C in 250 ml of methylene chloride 17 55 g of the product from the previous stage. 9.62 g of DMAP and 9 g of paranitrophenol chloroformate are added. The mixture is stirred for 1 hour and 1.40 g of paranitrophenol chloroformate are added. It is concentrated under reduced pressure. b) In a second flask under nitrogen at 0 ° C., the propargyloxylamine hydrochloride is suspended in

250 ml DMF. 6.7 g of sodium hydride are added. The reaction mixture is kept under stirring for 1 hour. The product prepared in stage a) is taken up with 250 ml of DMF at 0 ° C. to which the preceding solution is added. Stirring is continued for 1 hour. The reaction mixture is poured onto a mixture of aqueous sodium acid phosphate and ethyl ether solution. It is filtered, washed with ether and dried. 16.06 g of sought product is obtained.

Stage E: 3-amino-7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2-propynyl-oxy) -amino] carbonyl] -2-0- [(tetrahydro-2H-pyran-2- yl) oxy] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy-8 methyl- 2H-1-benzopyran-2 -one Dip into a bath of oil at 85 ° C, a suspension containing 16 g of the product of the previous stage, 22.7 g of sodium dithionite, 10.7 g of sodium acetate, 400 ml of water and 90 ml of ethyl alcohol. Stirring is continued for 60 minutes. We filter. The filtrate is kept for 2 hours in an ice bath. The crystals obtained are filtered off and washed with water. It is dried and 10.26 g of sought product is obtained.

Product P: 7- [[6-deoxy-5-C-methyl-4-0-methyl-2-0- (tetrahydro-2H-pyran-2-yl) -3-0- (triethylsilyl) - .alpha. -L- lyxo-hexopyranosyl] oxy] -4- (diphenylmethoxy) -8-methyl-2H-1- benzopyran-2-one

Stage A: 4- (diphenylmethoxy) -8 -methyl -7- (tetrahydro-2H- pyran-2 -yl) -2H-1-benzopyran-2 -one 55 g of 4-hydroxy-8-methyl-7- (tetrahydro-2H-pyran-2-yl) -2H-1-benzopyran-2-one are introduced into 250 ml of anhydrous dimethylformamide heated to 40 ° C., and added dropwise a solution of 58.3 g of diphenyldiazomethane in 250 ml of DMF. The addition is made in 3 hours while maintaining the temperature at 40 ° C. Several 3 g portions of diphenyldiazomethane are again added and the mixture is stirred for one hour at 40 ° C. The reaction medium is poured onto 2 l of sulfuric ether. The organic solution is washed with an aqueous sodium bicarbonate solution, with a sodium hydroxide solution (0.1 M), with water and with brine. It is evaporated to dryness. The residue is stirred in an isopropyl ether-hexane mixture (1-2). The insoluble matter is drained and dried. 20.5 g of sought product is obtained. CCM CH ₂ Cl ₂ -AcOEt (95-5). Rf = 0.44 Stage B: 4- (diphenylmethoxy) -7-hydroxy- 8 -methyl-2H-1- benzopyran-2 -one

35 ml of a 0.9 M hydrochloric acid solution in methanol are added to a solution containing a mixture of 20 g of product from stage A, 100 ml of dichloromethane and 100 ml of methanol. The mixture is stirred for 2 hours at room temperature and the solvents are evaporated. The residue is dispersed in absolute ethanol cooled to 0 ° C. The insoluble material is drained and rinsed with iced alcohol and then with sulfuric ether. Dried and collected 15.53 g of product which is dispersed in ether, drained and dried. 14.54 g of sought product is obtained. RMN ^X H MHz, CDC1 ₃ , ppm) δ 2.31 (8, 3H), 5.62 (s, 1H), 6.35 (s, 1H), 6.78 (d, 1H, J = _Hz), 7 , 75 (d, 1H, J = _Hz), 6.99 to 7.10 (m, _H), 7.30 to 7.42 (m, _H). Stage C: 7- [[6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo- hexopyranosyl] oxy] -4- (diphenylmethoxy) - 8 -methyl-2H-1- benzopyran-2 -one

A mixture of 91.13 g of stage B product, 58.6 g of 6-deoxy-5-C-methyl-4-0-methyl-L-lyxohexopyranose and 80 g of triphenylphosphine are cooled to 0 ° C. in 900 ml of dichloromethane. 60 ml of diisopropylazodicarboxylate are added dropwise. The mixture is stirred for 1 hour at room temperature. 34 g of triphenylphosphine are added and 25 ml of diisopropylazodicarboxylate. The mixture is stirred for 1 hour at room temperature. 34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate are added and the mixture is stirred for 12 hours at room temperature. Concentrate in vacuo. Chromatography eluting with a toluene / isopropyl alcohol mixture (95-5). After combining the fractions and evaporating the solvents, after recrystallization from isopropyl ether, 86.33 g of sought product is collected. ^X H NMR (300 MHz, CDC1 _3, ppm) δ l, 13 (s, 3H), 37 (s, 3H), 2.24 (s, 3H), 2.69 (s, 1H), 2 , 79 (s, 1H), 3.38 (d, 1H), J = 10 Hz), 3.60 (s, 3H), 4.24 (m, 1H), 4.28 (m, 1H), 5.56 (s, 1H), 5.64 (d, 1H, J = 1.5Hz), 6, (s, 1H), 7.18 (d, 1H), 7.81 (d, 1H) , 7.39 (m, 10H). Stage D: 7- [[6-deoxy-5-C-methyl-4-0-methyl-3-O- (triethylsilyl) -alpha-L-lyxo-hexopyranosyl] oxy] -4- (diphenylmethoxy) - 8-methyl-2H-1-benzopyran-2 -one

26.6 g of imidazole and 70.15 ml of diisopropylethylamine are added to a solution cooled to 0 ° C., containing 80 g of product from the previous stage and 600 ml of dichloromethane. 33.5 ml of triethylsilyl chloride are added dropwise. The mixture is stirred for 1 hour at room temperature. Washed with an aqueous solution of sodium dihydrogen phosphate, 1 M, with water and brine. It is dried over magnesium sulfate, filtered and concentrated. 98.58 g of product are collected which are purified by chromatography on silica eluting with a dichloromethane acetone mixture (from 0.8 to 1%). 46.5 g of product are obtained. ^X H NMR (300 MHz, CDCl ₃ -d6, ppm) δ 0.60 (q, _H, J = _Hz), 0.74 (q, _H, J = _Hz), 0.97 (t, _H, J = _Hz), 1.00 (t, _H, J = _Hz), 1.10 (S, 3H), 1.32 (s, 3H), 2.24 (s, 2H), 2.74 (s, 1H), 3.31 (d, 1H, J = _Hz), 3.54 (s, 3H), 4.07 (m, 1H), 4.29 (dd, 1H, J = Hz), 5.50 (s, 1H), 5.65 (d, 1H, J = Hz), 6.35 (s, 1H), 7.28 (d, 1H, J = Hz), 7, 81 (d, 1H, J = Hz), 7.40 (m). Stage E: 7- [[6-deoxy-5-C-methyl-4-0-methyl-2-O- (tetrahydro- 2H-pyran-2-yl) -3-0- (triethylsilyl) -alpha-L -lyxo- hexopyranosyl] oxy] -4- (diphenylmethoxy) -8-methyl -2H-1- benzopyran-2 -one 19 ml of dihydropyran and 400 mg of APTS are added to a solution containing 67 g of product from the previous stage and 1 l of dichloromethane. The mixture is stirred for 40 minutes at room temperature, 300 mg of APTS are added. After 30 minutes, 100 mg of APTS are added, then another 100 mg of APTS. The mixture is stirred for a further 20 minutes, then finely ground sodium hydrogen carbonate is introduced. Stirred for 10 minutes, dilute the reaction medium with a hexane / ethyl acetate mixture (1-2), wash with water and with brine. We dry. The solvents are filtered and evaporated. The product obtained is chromatographed, eluting with a heptane / ethyl acetate mixture (4-1). 77.9 g of sought product are collected. ^X H NMR (300 MHz, DMSO-d _6, ppm) δ 0.64 (q, _H, J = _Hz), 0.73 (q, _H, J = _Hz), 0.95 to 1.32 (_H ), 2.25 (s, _H), 2.27 (s, _H), 3.30 (d, _H, J = Hz), 3.4 (d, _H, J = Hz), 3.50 ( m, 2H), 3.93 (m, 2H), 3.53 (s, _H), 3.54 (s, _H), 4.04 to 4.15, 4.36 (dd, _H, J = _Hz), 4.94 (1), 4.96 (1), 5.50 (sl, H), 5.65 (sl), 6.37 (S, 1H), 7.15 (d, _H, J = _Hz), 7.19 (d, _HH, J = Hz), 7.81 (m, 1H), 7.30 to 7.44, 1.47 to 2.00.

EXAMPLE 4: 3-(2-Propynyloxy) -carbamic acid N- [7- [(6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy ester ] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran- 3-yl] -benzamide 60 μl of triethylamine and 50 μl of benzyl chloride are added to a solution containing 200 mg of product of the preparation 3 and 4 ml of methylene chloride. The mixture is stirred for 1 hour 30 minutes at 0 ° C. The temperature is allowed to rise to 20 ° C. Poured onto a mixture of ice and onosodium phosphate. It is extracted with methylene chloride, dried, filtered and concentrated. 400 ml of methanol are added at 20 ° C., 40 mg of TsOH, H ₂ O are added. The mixture is stirred for 2 hours at 20 ° C. Diluted with methylene chloride, washed with water, dried, filtered and concentrated. 90 mg of product are obtained. The aqueous phase is extracted with ethyl acetate, dried, filtered and concentrated. 75 mg of product are obtained. The 90 mg and 75 mg of product are combined. Chromatography on silica eluting methylene chloride, ethyl acetate, acetic acid 80- 20-1. 105 mg of sought product is obtained. EXAMPLE 5 3 (2-Propynyloxy) -carbamic acid 7- [(6-deoxy-6-C-methyl-4-0-methyl- .alpha. -L-mannopyranosyl) oxy] -4-hydroxy ester -3- [1- (methoxyimino) ethyl] 8-methyl-2H-1- benzopyran-3-yl] -2-one

Is dissolved at 20 ° C in 10 ml of methylene chloride, 139 mg of 2-methoxyiminopropanoic acid and 250 mg of pentafluorophenol. 270 mg of DCC are added in solution in 10 ml of methylene chloride. Stirred 2 hours 30 minutes at 20 ° C. Filtered, the filtrate is concentrated and redissolved in 10 ml of DMF. 5 ml of the solution thus obtained are stirred at 20 ° C. under a nitrogen atmosphere and 250 mg of product of preparation 3 are added. Stirred for 16 hours at 20 ° C. Diluted with methylene chloride, washed with water, dried, filtered and concentrated. The residue obtained is dissolved in 5 ml of methanol at 20 ° C. 80 mg of TsOH, 1H ₂ 0 are added. The mixture is stirred for 5 hours at 20 ° C. Purification is carried out by chromatography on silica, eluting with a mixture of methylene chloride, ethyl acetate, acetic acid 80-20-1 then hexane ethyl acetate 50-50. 100 mg of sought product is obtained, rf = 0.1. EXAMPLE 6: N- [7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2-propynyloxy) amino] carbonyl] -. alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy-8 methyl-2-oxo-2H-1-benzopyran-3-yl] -2- (2- pyridinylmethoxy) -acetamide Stage A: 2- [(2- pyridinyl) methoxy] -ethyl acetate

0.530 g of sodium hydride in a solution of 1 g of 2-hydroxymethylpyridine and DMF are added over 20 minutes at 0 ° C. 1.6 ml of ethyl chloroacetate are added at 0 ° C. 2 ml of a sodium acid phosphate solution are poured, then concentrated under reduced pressure. The product obtained is chromatographed on silica eluting with a 90-10 mixture of methylene chloride and methanol. 4.5 g of product are obtained which is chromatographed on silica eluting with a methylene chloride, methanol 90-10 mixture. The product obtained is purified and 1.30 g of sought product is obtained. Stage B: 2- [(pyridinyl) methoxy] acetic acid

3.7 ml of a 2N sodium hydroxide solution are added to a solution containing 1.3 g of the product prepared at the stage above and 10 ml of ethanol. Stirring is continued for 1 hour, brought to pH <7 by addition of a normal hydrochloric acid solution and concentrated under reduced pressure, taken up in acetone and filtered. The mother liquors are concentrated and 1.01 g of sought product is obtained. Stage C: N- [7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2-propynyloxy) amino] carbonyl] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy-8 methyl-2-oxo-2H-1-benzopyran-3-yl] -2- (2- pyridinylmethoxy) -acetamide Stirring is continued for 30 minutes, 0 , 2 g of product of preparation 3, 0.065 g of product from stage B, 0.053 g of HOBT and 0.075 g of EDCS and 6 ml of methylene chloride. Concentrated to dryness, a product is obtained which is chromatographed on silica eluting with methylene chloride methanol 90-10. 148 mg of product are obtained which is taken up in methanol, 40 mg of APTS is added. The product obtained is chromatographed, eluting with a 90-10 methylene chloride-methanol mixture. 0.110 g of sought product is obtained. EXAMPLE 7 3 (2-Propynyloxy) -carbamic acid N- [7- [(6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy ester ] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2- [(1,2,5-thiadiazol-3-yl) oxy] -acetamide Stage A: Acid 2 - [1, 2, 5-thiadiazol-3-yl) oxy] -acetic 5.93 ml of a 2N sodium hydroxide solution is added to a solution containing 1 g of ethyl acid ester 2- [1, 2,5-thiadiazol-3-yl) oxy] -acetic and 5 ml of ethanol. Stirring is continued for 2 hours. It is brought to pH5-6 by addition of a normal solution of hydrochloric acid. Concentrate and obtain 1.054 g of product. Chromatography on silica eluting with a mixture of methylene chloride and methanol 90-10.

Stage B: (2-Propynyloxy) -carbamic acid 3 '-N- [7- [(6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy ester ] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2- [(1, 2, 5-thiadiazol-3-yl) oxy] -acetamide

0.105 g of the product from the preceding stage is poured at 0 ° C. into 10 ml of methylene chloride. We add 2 drops of DMF and add 0.126 ml of oxalyl chloride. Stirring is continued for 30 minutes. It is concentrated under reduced pressure and taken up in methylene chloride. 0.164 ml of pyridine and 0.200 g of the product of preparation 3 are added to 10 ml of methylene chloride. Stirring is continued for 20 minutes. Poured onto an ice-cold solution of sodium chloride. It is extracted with methylene chloride and dried. A product is obtained which is chromatographed on silica, eluting with a 90-10 methylene chloride-methanol mixture. 76 mg of product are obtained which is taken up in 4 ml of methanol. 22 mg of APTS are added and the mixture is stirred for 30 minutes. It is concentrated under reduced pressure. The product obtained is purified by chromatography on silica, eluting with a methylene chloride, methanol 95-5 mixture. 30 mg of sought product is obtained.

By operating as above, the following products were obtained:

- (2-Propynyloxy) -carbamic acid 3 '-N- ester [7- [(6-deoxy- 5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] - 4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2- [(5-methyl-isothiazol-3-yl) oxy] -acetamide

- (2-Propynyloxy) -carbamic acid 3 '-N- ester [7- [(6-deoxy- 5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] - 4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2- [[2 '-ethyl- [2,5' -bithiazol] -4-yl) methoxy] -acetamide

- (2-Propynyloxy) -carbamic acid 3 '-N- ester [7- [(6-deoxyoxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2- [(1- oxido-2-pyridinyl) methoxy] -acetamide - (trans) -Acid (2-propynyloxy) -carbamic 3 '-ester of N- [7- [(6-deoxy-5-C- methyl-4-0-methyl- .alpha. -L-lyxo hexopyranosyl) oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran- 3-yl] -2, 2-dimethyl- 3- (2-methylpropyl) -cyclopropanecarboxamide

- (1R-trans) (2 -propynyloxy) -carbamic acid 3'-ester of N- [7- [(6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo- hexopyranosyl) oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran- 3-yl] -2,2-dimethyl-3 -ethyl-cyclopropanecarboxamide

- (2-Propynyloxy) -carbamic acid 3 '-N- ester [7- [(6-deoxy- 5-C-methyl-4-0-methyl-. alpha. -L-lyxo-hexopyranosyl) oxy] -4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -2 -phenoxy- acetamide

- (2 -propynyloxy) -carbamic acid 3 '-N- ester [7- [(6-deoxy- 5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] - 4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -benzamide

- (2 -propynyloxy) -carbamic acid 3 '-N- ester [7- [(6-deoxy- 5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] - 4- hydroxy-8-methyl-2 -oxo-2H-1-benzopyran-3 -y1] -2-propyl- cyclopropanecarboxamide

- Trans-acid (2 -propynyloxy) -carbamic 3 '-ester of N- [7- [(6-deoxy-5-C-methyl-4-0-methyl-. Alpha. -L-lyxo-hexopyranosyl) oxy ] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2-

(methoxymethyl) -cyclopropanecarboxamide - Trans-acid (2 -propynyloxy) -carbamic 3 '-ester of 2-

(butoxymethyl) -N- [7- [(6-deoxy-5-C-methyl-4-0-methyl-. alpha.L- lyxo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-2-oxo -2H-1- benzopyran-3 -yl] -cyclopropanecarboxamide

- (2 -propynyloxy) -carbamic acid 3 '-N- ester [7- [(6-deoxy- 5-C-methyl-4-0-methyl- .alpha. -Lyxo-hexopyranosyl) oxy] -4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -benzeneeacetamide

- (2-Propynyloxy) -carbamic acid 3 '-N- ester [7- [(6-deoxy- 5-C-methyl-4-0-methyl- .alpha. L-lyxo-hexopyranosyl) oxy] -4 - hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2- (1-hydroxy- Propyl) -cyclopropanecarboxamide

- (2-Propynyloxy) -carbamic acid 3 '-N- ester [7- [(6-deoxy- 5-C-methyl-4-0-methyl- .alpha. L-lyxo-hexopyranosyl) oxy] -4 - hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2- [(phenylmethoxy) methyl] -cyclopropanecarboxamide

- (2-Propynyloxy) -carbamic acid 3 '- N-1-oxide ester [7- [(6-deoxy-5-C-methyl-4-0-methyl-. Alpha .L-lyxo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -4- pyridinecarboxamide - (2-Propynyloxy) -carbamic acid 3 '-N-oxide ester [ 7- [(6-deoxy-5-C-methyl-4-0-methyl- .alpha. L-lyxo-hexopyranosyl) oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran- 3-yl] -3- pyridinecarboxamide - 7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0 [[(2-propynyloxy) amino] carbonyl] - .alpha. L-lyxo-hexopyranosyl] oxy] -4-hydroxy-8- methyl-2-oxo-2H-1-benzopyran-3-carbamate 2-propenyl

- (2 -propynyloxy) -carbamic acid 3 '- N [7- [(6-deoxy- 5-C-methyl-4-0-methyl- .alpha. L-lyxo-hexopyranosyl) oxy] ester -4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -5-thiazolecar- boxamide

- N- [7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2-propynyloxy) amino] carbonyl] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy- 8-methyl-2-oxo-2H-1-benzopyran-3-yl] -alpha- (hydroxymethyl) - benzeneeacetamide (isomer A)

- N- [7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2 -propynyloxy) amino] carbonyl] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy- 8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -alpha- (hydroxymethyl) - benzeneacetamide (isomer B)

- N- [7- [[6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo- hexopyranosyl] oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran- 3-yl] -4-methyl-1-piperazinecarboxamide

- N- [7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2 -propynyloxy) amino] carbonyl] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy-

8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -3-hydroxy-2-phenoxy-propanamide (isomer A)

- 7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2-propynyloxy) amino] carbonyl] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy- 8-methyl-2-oxo-2H-1-benzopyran-3-yl] -3-hydroxy-2-phenoxy-propanamide (B isomer)

- N- [7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2 -propynyloxy) amino] carbonyl] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy- 8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -5-methyl-4-hexenamide - N- [7- [[6- deoxy-5-C-methyl-4-0-methyl-3-0- [[(2 -propynyloxy) amino] carbonyl] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy- 8-methyl-2-oxo-2H-1-benzopyran-3 -yl] -2,2, 2-trifluoro-acetamide Preparation 4: 6-deoxy-5 -C-ethyl-6-C-methyl-4-0-methyl-2,3- O- (1-methyl ethylidene) -L-lyxohexopyranose

Stage A: [4S- [4-. alpha. , 5- .alpha. (S *)]] -β, β-diethyl-2, 2-dimethyl-5- (hydroxymethyl) -α-methoxy-1, 3-dioxolan-4-ethanol Introduced into 250 ml of tetrahydrofuran (THF) 400 ml of 1 M ethyl magnesium bromide dissolved in THF, stirred for 15 minutes, then 25.2 g of .Delta are introduced. -actone of 2-0-methyl-3, 4-0- (1-methyl-ethylidene) -L-arabinonic acid and 126 ml of THF. The mixture is stirred for 1 hour 30 minutes while returning to ambient temperature. The reaction medium is poured onto 480 g of an ice-water mixture (1: 1) and stirred for 15 minutes. The aqueous phase is decanted and 80 g of sodium chloride is added thereto. The aqueous phase is re-extracted with methylene chloride. The organic phases (THF + methylene chloride) are combined, dried over sodium sulfate, filtered and then evaporated to dryness under vacuum in a bath at 50 ° C. Dried and obtained 32.9 g of the desired product. Stage B: .Delta. -5-C-ethyl-6-C-methyl-4-O-methyl-2, 3-0- (1-methylethylidene) -L-lyxonic lactone It is introduced into 450 ml of methylene chloride,

450 ml of dimethylsulfoxide (DMSO), 246 ml of triethylamine (TEA) and 45.6 g of the product obtained according to stage A. 90 g of trioxide sulfide complex are added in portions while maintaining the temperature below 30 ° C. pyridine. Stirring is continued for 2 hours 30 minutes. Then 500 ml of ether are introduced and the reaction medium is poured onto 500 g of ice + water (1: 1). Decanted, the aqueous phase is reextracted with 500 ml of ether. The organic phases are combined, dried over sodium sulfate, filtered and then evaporated to dryness under vacuum. 66 g of product are obtained. 250 ml of ether are re-extracted with 3 times and washed with 150 ml of water. The organic phases are again combined, dried over sodium sulfate, filtered and then evaporated to dryness under vacuum. 39 g of sought product is obtained. Stage C: 6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl-2, 3-0- (1- methyl ethylidene) -L-lyxohexopyranose

39 g of the product from the preceding stage are introduced into 390 ml of tetrahydrofuran (THF). The reaction medium is cooled to 0 ° C., then, while maintaining the temperature at 0 ° C., 120 ml of a 1.5 M solution of DIBAH in toluene are introduced. The mixture is stirred for 1 hour 30 minutes while allowing the temperature to rise. Poured onto the reaction medium while keeping the temperature below 20 ° C., 500 ml of a 1 M aqueous solution of tar- double tare of sodium and potassium. The mixture is stirred for 1 hour at room temperature. Decanted, the aqueous phase is reextracted with methylene chloride. The organic phases are combined (THF + methylene chloride), dried over magnesium sulfate, filtered and then evaporated to dryness. 38.46 g of sought product is obtained.

Stage D: 6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl-L- lyxohexopyranose

67.7 g of product from the preceding stage, 183 ml of 0.1N sulfuric acid are introduced into 183 ml of water. The mixture is heated to 70 ° C. for 2 hours 30 minutes. The mixture is allowed to return to ambient temperature and then barium carbonate to bring the pH to around 7-8. The medium is filtered. Rinse with 60 ml of water. The filtrate is concentrated under vacuum at 45 ° C. The residue is taken up in 50 ml of ethyl acetate and then evaporated to dryness under vacuum. The operation is repeated three times always with 50 ml of AcOEt. The oil obtained is dissolved in 50 ml of methylene chloride. We filter again. After evaporating the methylene chloride, 55.87 g of product are obtained. It is taken up in 80 ml of ether and stirred for 3 hours at room temperature. It is drained, rinsed with a minimum of ether and then dried in an oven under vacuum at 45 ° C. 28.32 g of sought product is obtained, F = 100 ° C. EXAMPLE 8 N- [7- [[6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl-3- O- [(5-methyl-1H-pyrrol-5-yl) carbonyl) - .alpha. -L-lyxo- hexopyranosyl) oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran- 3-yl] -2-methyl-propanamide

Stage A: 2, 3-cyclic carbonate of 6-deoxy-5-C-ethyl-6-C-methyl-4-O-methyl-L-lyxohexopyranose A mixture of 3.083 g of 6- is cooled to 0 ° C. deoxy-5- C-ethyl-6-C-methyl-4-0-methyl-L-lyxohexopyranose and 50 ml of methylene chloride. 3.4 g of 1.1 carbonyldiimidazole and 0.168 ml of 1.8-diazo-bicyclo [5-4-0] -undec-7-ene are added. Poured onto 30 ml of a 1M sodium hydrogenphosphate solution and extracted with methylene chloride. The organic phases are washed with water, dried, filtered and concentrated. 4.09 g of crude sought product is obtained, which is used as it is in the following stage. Stage B: 2, 3 -cyclic carbonate and 1- (2, 2, 2-trichloro ethanimidate) of 6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl-L- lyxo-hexopyranoside

3.05 g of trichloroacetonitrile are added dropwise in a mixture of 78 mg of cesium carbonate, 20 ml of methylene chloride and 3.97 g of product from stage A The mixture is stirred for 16 hours at room temperature. We filter and concentrate. 5.29 g of sought product is obtained. Stage C: 7- [(2,3-0-carbonyl-6-deoxy-5-C-ethyl-6-C-methyl-4- O-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] - 4-hydroxy-8- methyl-3- (phenylazo) -2H-1-benzopyran-2-one

0.13 ml of boron trifluoride etherate [BF ₃ (OEt) ₂ ] is introduced into a mixture containing 90 ml of methylene chloride, 3.10 g of 4,7-dihydroxy-8-methyl-3- ( phenylazo) -2H-1-benzopyran-2-one and 4.7 g of product from the previous stage. We filter and concentrate. 7.05 g of a product are obtained which is purified by FLASH chromatography on silica eluting with a methylene chloride isopropanol 95-5 mixture. A product is obtained which crystallizes from ether, spins and dries under reduced pressure. 2.32 g of sought product is thus obtained.

Stage D: 3-amino-7- [(2,3-0-carbonyl-6-deoxy-5-C-ethyl-6-C- methyl-4-O-methyl- .alpha. -L-lyxo-hexopyranosyl ) oxy] -4- hydroxy-8-methyl-2H-1-benzopyran-2-one A mixture of 2.32 g of product from stage C 200 is placed under hydrogen pressure (approximately 1400 m bar) for 2 hours ml of ethanol and 232 mg of palladium on carbon at 10%. Filtered, washed with an ethanol mixture of methylene chloride and concentrated in a rotary evaporator under reduced pressure. 1.54 g of product are obtained.

Stage E: N- [7- [(2,3-0-carbonyl-6-deoxy-5-C-ethyl-6-C-methyl- 4-O-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4-hydroxy-8- methyl-2-oxo-2H-1-benzopyran-3 -yl] -2-methyl-propanamide 0.55 ml of pyridine and 0.4 ml of chloride are introduced dropwise isobutyryl in a mixture of 1.5 g of product from the previous stage and 30 ml of methylene chloride. Stirring is continued for one hour. Poured onto 20 ml of a 1 M sodium hydrogen phosphate solution, extract with methylene chloride. The organic phases are washed, dried, filtered and concentrated. 1.8 g of sought product is obtained.

Stage F: N- [7- [(6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4-hydroxy-8 -methyl-2-oxo- 2H-1-benzopyran-3 -yl] -2 -methyl-propanamide

A solution containing 303 mg of product from the preceding stage, 5 ml of methanol and 1.4 ml of a 0.5N aqueous sodium hydroxide solution is stirred for 2 hours. 50 ml of an aqueous solution are poured 1 M sodium hydrogenophosphate, methylene chloride extract. Wash with water, dry, filter and concentrate. 270 mg of sought product is obtained. Stage G: N- [7- [[6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl-3-0- [(5-methyl-1H-pyrrol-5-yl) carbonyl) - .alpha. -L-lyxo- hexopyranosyl) oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran- 3-yl] -2-methyl-propanamide

Stirred for 4 hours at room temperature 260 mg of product from the preceding stage, 4 ml of dimethylformamide, 0.168 ml of (1, 8-diaza-bicyclo [5-4-0] - undec-7-ene) and 152 mg 2- 2-2-trichloroethyl 5-methyl 2-pyrrolcarboxylate. Poured onto 20 ml of a 1 M aqueous sodium hydrogenophosphate solution, extracted with ethyl acetate. The organic phases are combined, dried, filtered and concentrated. 260 mg of crude sought product is obtained which is purified by chromatography on silica eluting with methylene chloride methanol 95-5 mixture. 110 mg of this product are taken and 27 microliters of 1,8-diaza-bicyclo [5.4.0] -undec-7-ene and 3 ml of methylene chloride are added thereto. The mixture is stirred for 1 hour at room temperature. It is poured into 3 ml of an aqueous solution of sodium hydrogenophosphate 1 M. It is extracted with methylene chloride. The organic phases are washed with water, combined and dried over magnesium sulfate, filtered and concentrated. 100 mg of sought product is obtained. Mp 140-142 ° C.

EXAMPLE 9 Acid (2-propynyloxy) -carbamic 3 '-ester of N- [7- t (6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl- .alpha.L- lyxo- hexopyranosyl) -oxy] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran- 3-yl] -2-methyl-propanamide

303 mg of the product prepared in the penultimate stage of the previous example, 3 ml of pyridine, 60 mg of lithium perchlorate and 610 mg of O-propargyl hydroxylamine hydrochloride are stirred for 50 hours at room temperature. It is kept in the freezer for 3 days and stirred again for 4 hours. It is poured into 10 ml of water and extracted with methylene chloride. The organic phases are washed, dried over magnesium sulfate, filtered and concentrated. 420 mg of product are obtained which is purified by chromatography on silica (eluent methylene chloride-methanol 95-5). 170 mg of a 3/2 regioisomer product are obtained in a 75-25 mixture. Preparation 5: [7R- (7.alpha., 8.beta., 9.beta., 10.alpha.)] -4- hydroxy) -7- [[10-methoxy-8- [(tetrahydro-2H- pyran-2-yl) oxy] -9- [(triethylsily) -oxy] -6-oxaspiro [4.5] decan-7-yl) oxy] -8-methyl- 2H-1-benzopyran-2-one Stage A: [4S- [4. alpha. , 5. alpha. (S *)]] -2, 2-dimethyl-5- [(1- hydroxyclopentyl) methoxymethyl] -1, 3-dioxolane-4-methanol 20 ml of a dibromobutane solution (106 ml of dibromobutane in 200 are introduced ml of THF), in a mixture containing 43 g of magnesium, 100 ml of THF and an iodine crystal. The reaction mixture is placed under ultrasound. 1.7 L of THF are added. The rest of the dibromo solution is added. Stirring is continued for 2 hours 30 minutes. A solution containing 80.37 g of delta-lactone of 2-0-methyl-3,4,4-0- (1-methylethylidene) -L acid is added at 17 ° C. - arabic and 1 liter of THF. The mixture is stirred for 4.5 hours at room temperature. Cool to 0 ° C, add a saturated solution of ammonium chloride. Decanted, the organic phase is drawn off, extracted with a 20% ethyl acetate solution of heptane. Wash, dry and evaporate to dryness. 111.85 g of sought product is obtained. Stage B: [3 'As- (3' a. Alpha., 7 '. Alpha, 7' a .beta.)] -7 '-methoxy- dihydro-spiro [cyclopentane-1, 6' - [6H] - 1, 3-dioxolo [4,5- c] pyran] -4 '(3aH) -one

221 g of PyS03 are added to a solution containing 111 g of the product prepared in stage A and a mixture of one liter of methylene chloride, 1 liter of DMSO, 0.607 1 of triethylamine. The mixture is stirred for 2 hours at room temperature. Poured onto an aqueous solution of sodium acid phosphate, extracted with an ethyl acetate, heptane (1-1) mixture. It is dried, filtered and evaporated to dryness. 57.7 g of sought product is obtained.

Stage C: [8R- (8.alpha., 9.alpha, 10.beta)] -10-methoxy-6- oxaspiro [4.5] -decane-7, 8, 9-triol Add at -5 ° C, 157 ml of a 1.5 M solution of dibutylaluminum hydride in toluene in a solution containing 56 g of the product of the previous stage and 300 ml of THF. The mixture is stirred at -3 ° C for 1 hour. 1 liter of a 1 M solution of double sodium and potassium tartrate is added. The mixture is stirred for 15 minutes at room temperature. The reaction medium is extracted with an ethyl acetate-heptane 1-1 mixture. Wash with water, brine, dry and evaporate to dryness. The residue obtained is stirred at 70 ° C. in the presence of 150 ml of a 0.1 N sulfuric acid solution and 150 ml of water for 2.5 hours. Cool to room temperature. It is filtered and evaporated to dryness. 49 g of the sought product are obtained. Stage D: [7R- (7. alpha., 8.beta., 9.beta., 10. alpha.)] -7- [(8,9- dihydroxy-10-methoxy-6-oxaspiro [4.5] - decan-7-yl) oxy] -4- (diphenylmethoxy) -8-methyl-2H-1-benzopyran-2 -one 45.30 g of DIAD is added dropwise at 0 ° C in a mixture of 49 g of product of preparation 3, 73 g of 4- (diphenylmethoxy) -7-hydroxy-8-methyl-2H-1-benzopyran-2-one prepared as indicated in preparation 6 and 59 g of triphenylphosphine. The mixture is stirred for 1.5 hours at room temperature. 1 equivalent of triphenylphosphine and DIAD is added at 0 ° C. The solvents are evaporated, taken up in ether and the desired product is obtained.

Stage E: [7R- (7. alpha., 8.beta., 9.beta., 10. alpha.)] -4- (diphenyl-methoxy) -7- [[8-hydroxy-10-methoxy-9 - [(triethylsily) oxy] -6-oxaspiro [4.5] -decan-7-yl) oxy] -8-methyl- 2H-1-benzopyran-2-one

15.21 g of triethylsilane chloride are added at 0 ° C. in a solution containing 48 g of the product from the previous stage. tooth and 400 ml of methylene chloride. The mixture is stirred for 1 hour at 0 ° C., washed with a 1 M solution of sodium acid phosphate and rinsed with water. We dry. The product obtained is chromatographed on silica, eluting with a methylene chloride acetone 99-1 mixture and then with a toluene terbutylmethyl ether mixture. 28.37 g of the desired product are obtained. Stage F: [7R- (7. alpha., 8. beta., 9. beta., 10. alpha.)] -4- (diphenyl-methoxy) -7- [[10-methoxy-8- [(tetrahydro -2H-pyran-2- yl) oxy] -9- [(triethylsily) oxy] -6-oxaspiro [4.5] -decan-7- yl) oxy] -8-methyl-2H-1-benzopyran-2-one

7.57 ml of 2,3-dihydropyran and 400 mg of paratoluene sulfonic acid are added to a solution containing 28.1 g of the product from the previous stage and 250 ml of dichloromethane. The mixture is stirred for 1 hour at room temperature. Baking soda is added and the mixture is stirred for 20 minutes at room temperature. Wash with water, dry the organic phases over sodium sulfate. The product obtained is chromatographed on silica eluting with a heptane-ethyl acetate mixture 4.1. 16.81 g of sought product is obtained. Stage G: [7R- (7. alpha., 8.beta., 9.beta., 10. alpha.)] -4- hydroxy) -7- [[10-methoxy-8- [(tetrahydro-2H- pyran-2-yl) oxy] -9- [(triethylsily) -oxy] -6-oxaspiro [4.5] -decan-7-yl) oxy] -8- methyl-2H-1-benzopyran-2 -one

A solution of 16.19 g of the product of the preceding stage, 150 ml of THF, is stirred under a hydrogen atmosphere, in the presence of 810 mg of palladium on carbon. Filtered and 15.1 g of sought product is obtained.

Preparation 6: 4- (diphenylmethoxy) -7-hydroxy-8-methyl-2H-1-benzopyran-2-one Stage A: 4- (diphenylmethoxy) -8-methyl- 7- (tetrahydro-2H- pyran-2- yl) -2H-1-benzopyran-2 -one

55 g of 4-hydroxy-8-methyl- 7- (tetrahydro-2H-pyran-2-yl) -2H-1-benzopyran-2-one are introduced into 250 ml of anhydrous dimethylformamide heated to 40 ° C., and added dropwise a solution of 58.3 g of diphenyldiazomethane in 250 ml of DMF. The addition is made in 3 hours while maintaining the temperature at 40 ° C. Several 3 g portions of diphenyldiazomethane are again added and the mixture is stirred for one hour at 40 ° C. We pour the reaction medium onto 2 1 of sulfuric ether. The organic solution is washed with an aqueous sodium bicarbonate solution, with a sodium hydroxide solution (0.1 M), with water and with brine. It is evaporated to dryness. The residue is stirred in an isopropyl ether-hexane mixture (1-2). The insoluble matter is drained and dried. 20.5 g of sought product is obtained. CCM CH ₂ Cl ₂ -AcOET 59565 °. Rf = 0.44.

Stage B: 4- (diphenylmethoxy) -7 -hydroxy- 8-methyl-2H-1-benzopyran-2 -one 35 ml of a 0.9 M hydrochloric acid solution in methanol is added to a solution containing a mixture of 20 g of stage A product, 100 ml of dichloromethane and 100 ml of methanol. The mixture is stirred for 2 hours at room temperature and the solvents are evaporated. The residue is dispersed in absolute ethanol cooled to 0 ° C. The insoluble material is drained and rinsed with iced alcohol and then with sulfuric ether. Dried and collected 15.53 g of product which is dispersed in ether, drained and dried. 14.54 g of sought product are obtained 1H NMR (300 MHz, CDC13, ppm) δ 2.31 (s, 3H), 5.62 (s, 1H), 6.35 (s, 1H), 6.78 (d, 1H, J = _Hz), 7.75 (d, 1H, J = _Hz), 6.99 to 7.10 (m, _H), 7.30 to 7.42 (m, _H). EXAMPLE 10: [7R- (7, α., 8. Β, 9.β, 10.α)] - (2-propynyloxy) - 8-hydroxy-7- [4-hydroxy-8-methyl-2-carbamate -oxo-3- (benzoylamino) -2H-l-benzopyran-7-yl) -10-methoxy-6- oxaspiro [4.5] decan-9-yl

Stage A: [7R- (7.α., 8.β, 9.β, 10.α)] -4-hydroxy-7- [[10- methoxy-9- [(triethylsilyl) oxy] -6-oxaspiro [4.5] decan-7-yl] oxy] -8-methyl-3- (phenylazo) -2H-1-benzopyran-2-one In aqueous hydrochloric acid solution (27 ml) cooled to 0 ° C, add aniline (1.44 ml) drop by drop. This mixture is stirred at 0 ° C for five minutes. The aqueous sodium nitrite solution (1.18 g: dissolved in 10 ml of water) is then introduced dropwise. After 20 minutes of stirring at 0 ° C., sodium acetate (8.41 g) is added and the mixture is stirred for a further 10 minutes. Ethanol (30 ml) is then added. Still at 0 ° C., a solution of [7R- (7.α., 8.β, 9.β, 10.α)] -4-hydroxy-7- [[10-methoxy-8- [(tetrahydro-2H-pyran-2- yl) oxy] -9- [(triethylsilyl) oxy] -6-oxaspiro [4.5] decan-7-yl] oxy] -8-methyl-2H-1-benzopyran-2-one of preparation 5, 13.15 mmol in 30 ml of THF. This mixture is stirred for forty minutes at 0 ° C. The reaction solution is poured onto an aqueous solution of sodium dihydrogen phosphate (1M: 100 ml). Extraction is carried out with an AcOEt-heptane mixture (1: 1). The organic solution is washed with water and then dried over sodium sulfate, filtered and concentrated to dryness. The desired product is thus collected.

Stage B: [7R- (7.α., 8.β, 9.β, 10.α)] -7- [(8,9-dihydro-10- methoxy-6-oxaspiro [4.5] decan-7- yl] oxy] -4-hydroxy-8-methyl-3- (phenylazo) -2H-1-benzopyran-2-one

To a solution, cooled to 0 ° C., of the above product in anhydrous tetrahydrofuran (170 ml), a solution of tetrabutylamonium fluoride (1M in THF; 20 ml) is added dropwise. The temperature is allowed to rise and stirred for 1 hour at room temperature. Again added tetrabutylamonium fluoride (1M in THF: 20 ml) and stirred for an additional hour. The reaction solution is poured onto an aqueous solution of sodium dihydrogen phosphate (100 ml). Extraction is carried out with an AcOEt-heptane mixture (80-20). The organic solution is washed with water and then dried over magnesium sulphate, filtered and concentrated to dryness. 9 g of crude product are collected which are purified by chromatography, eluting with a dichloromethane-acetone mixture (94: 6).

Stage C: [3'aR- (3'a.α., 4'α., 7'α., 7'a.α)] -4 '- [[4-dihydro-8- methyl-3- ( phenylazo) -2H-1-benzopyran-7-yl] oxy] -7 '-methoxy- tetrahydro-spiro [cyclopentane-1, 6' [6H-1, 3] dioxolo [4, 5- c] pyran] -2 '-one

The mixture of stage B product (2.42 g) and carbonyldiimidazole (1.6 g) in anhydrous tetrahydrofuran (30 ml) is heated to reflux. After forty five minutes, the cooled reaction mixture is poured onto an aqueous solution of sodium hydrogen sulphate (10% sol.: 20 ml) then extracted with dichloromethane. The organic phase is dried over magnesium sulfate. We filter and evaporate until dryness. The residue is purified by chromatography on silica, eluting with a dichloromethane-acetone mixture (95-5). 2.35 g of the desired product are collected. Stage D: [3 'aR- (3' a.α., 4 'α., 7' α., 7 'a.α.)] -4' - [[3-amino-4-hydroxy-8- methyl-2-oxo-2H-1-benzopyran-7-yl] oxy] -7 '-methoxy- tetrahydro-spiro [cyclopentane-1, 6' [6H-1, 3] dioxolo [4, 5-c] pyran ] -2 '-one

The solution of product from the previous stage in tetrahydrofuran (30 ml) is vigorously stirred at room temperature, in the presence of Pd / C (0.250 G: 10%), under a hydrogen atmosphere. After forty minutes the reaction is complete. The catalyst is removed by filtration. Evaporate to dryness. The residue is concretized in an ether-pentane mixture under ultrasound and then isolated by filtration. After drying, 1.85 g of sought product is recovered.

Stage E: [3'aR- (3 'a.α., 4'α., 7'α., 7'a.α.)] -N- [4-hydroxy-7- [(7' -methoxy -2 '-oxo-tetrahydro-spiro [cyclopentane-1, 6' [6H- 1,3] dioxolo [4, 5-c] pyran] -4 '-yl) oxy] -8-methyl-2-oxo- 2H-1- benzopyran-3-yl] -benzamide

Triethylamine (177 μl) is added dropwise to the suspension cooled to 0 ° C. of product from the preceding stage in dichloromethane (5 ml). 134 μl of benzoyl chloride are added to the syringe. The reaction solution is stirred for 1 hour at 0 ° C. Again triethylamine (18 μl) and benzoyl chloride (13 μl) are added and the reaction mixture is stirred for an additional hour at 0 ° C. The reaction solution is poured onto an aqueous solution of sodium dihydrogen phosphate (1 M: 100 ml). Extraction is carried out with an AcOEt-heptane mixture (80:20). The organic solution is washed with water and then dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography, eluting with a heptane-ethyl acetate mixture (2: 1). 420 mg of sought product is obtained.

Stage F: [7R- (7.α., 8 β., 9 β., 10.α)] - (2-propynyloxy) - 8-hydroxy-7- [4-hydroxy-8-methyl-2-carbamate -oxo-3- (benzoylamino) -2H-1-benzopyran-7-yl] -10-methoxy-6- oxaspiro [4.5] decan-9-yle

To a solution of product of the preceding stage in pyridine (dried over potassium hydroxide; 4 ml) is added successively O-propargylhydroxyamine (822 mg) and lithium perchlophleen (82 mg). The reaction medium is stirred 2.5 days at room temperature. The reaction solution is poured onto an aqueous solution of sodium hydrogen sulfate (10%: 100 ml). Extraction is carried out with an AcOEt-heptane mixture (80-20). The organic solution is washed with water and then dried over magnesium sulphate, filtered and concentrated to dryness. 497 mg of crude desired product is obtained which is chromatographed on silica eluting with a dichloromethane-methanol mixture (94: 6). 263 mg of sought product is obtained. EXAMPLE 11: [7R- (7.α., 8 β., 9 β., 10.α)] - (2-propynyloxy) - carbamate of 7- [4-hydroxy-8-methyl-3- [(2 -methyl1-1-oxopropyl) amino] -2-oxo-2H-1-benzopyran-7-yl] -10-methoxy-6-oxaspiro [4.5] decan-9-yle Stage A: [3'aR- (3'a.α., 4'α., 7'α., 7'a.α.)] -N- [4-hydroxy-7- [(7 '-methoxy-2' -oxo-tetrahydro- spiro [cyclopentane-1, 6 '[6H- 1,3] dioxolo [4, 5-c] pyran] -4' -yl) oxy] -8-methyl-2-oxo-2H-1- benzopyran-3 - yl] -2 -methylpropanamide

Hydrogenation is carried out for 2 hours under an atmosphere of H ₂ in the presence of palladium on carbon a solution of 810 mg of product of stage C of the preceding example, namely [3'aR- (3'a. α., 4'α., 7'α., 7'a.α.)] -4 '- [[4-hydroxy -8- methyl-3-phenylazo) -2-oxo-2H-1-benzopyran- 7-yl] oxy] - 1 '- methoxy-tetrahydro-spiro [cyclopentane-1, 6' [6H-1, 3] dioxolo- [4, 5-c] pyran] -2 '-one to obtain the product 3 - corresponding amino. It is filtered, rinsed with THF and the solvent is evaporated. 10 ml of methylene chloride, 240 μl of triethylamine and then 165 μl of isopropyl acid chloride are added at 0 ° C. The mixture is stirred for 1 hour at 0 ° C., diluting with methylene chloride and washing with sodium acid phosphate. Chromatography on silica eluting with a hexane / ethyl acetate mixture 2-1 and 680 mg of sought product is obtained. Stage B: [7R- (7.α., 8 β., 9 β., 10.α)] - (2 -propynyloxy) - carbamate of 7- [4-hydroxy-8-methyl-3- [(2 -methyl-l-oxo- propyl) amino] -2-oxo-2H-1-benzopyran-7-yl] -10-methoxy-6-oxaspiro [4.5] decan-9-yl

A solution containing 680 mg of the preceding stage product, 1.4 g of o-propargyl hydroxylamine and 139 mg of lithium perchlorate and 6 ml of pyridine is stirred at ambient temperature for 2 and a half days. The reaction solution is poured onto a 10% aqueous sodium hydrogensulfate solution and extracted with a hexane-ethyl acetate 1-1 mixture. The organic phase is dried and the solvents are evaporated. The product obtained is chromatographed on silica eluting with a methylene chloride / ethyl acetate / acetic acid 80-20-1 mixture and 310 mg of sought product is obtained.

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS Tablets containing:

Product of Example 10 150 mg

Excipient q.s.p. 1 g

Details of excipient: starch, talc, magnesium stearate Product of Example 11 150 mg

Excipient q.s.p. 1 g

Details of the excipient: starch, talc, magnesium stearate

Injectables have also been prepared from salified products.

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

A - Method of dilutions in liquid medium

A series of tubes has been prepared in which the same quantity of sterile nutritive medium is distributed. Increasing quantities of the product to be studied are distributed in each tube, then each tube is seeded with a bacterial strain. After incubation for 24 hours in an oven at 37 ° C, the growth inhibition is assessed by transillumination, which makes it possible to determine the minimum inhibitory concentrations (MIC) expressed in micrograms / cm ³ . In vitro activity

CM1 in μg / ml

On the following strains

EX. 10 EX. 11 Staph.aureus 011HT18 <0.04 <0.04

Staph. epidermidis 0126042 <0.04 <0.04

Staph. Coag. Negative 012HT5 0.08 0.15

Strepto. pyogene 02A1UC1 0.16 0.08

Strepto pneumoniae 030BI2 <0.04 <0.04 Entero faecium 02D3IP2 0.63 0.32

Entero faecalis 02D2UC5 1.2 0.63

The products of Examples and in particular the products of Examples 10 and 11 show excellent activity.

B - Inhibition of gyrase B The products are inhibitors of gyrase B; the dose at 50% of the DNA supercoiling is less than 5 μg / ml.

Claims

1) The compounds of formula (I):

in which

Ri represents an alkyl, alkenyl or alkynyl, 0-alkyl, O-alkenyl or O-linear or branched or cyclic O-alkynyl radical containing up to 8 carbon atoms optionally substituted by one or more halogen atoms, optionally interrupted by a d atom sulfur or nitrogen oxygen, an aryl or aralkyl radical containing up to 18 optionally substituted carbon atoms, an heterocyclic radical, aromatic or not, mono or polycyclic optionally substituted, an NH ₂ , NHalci or NHalc ₂ , NHalc ₃ radical or NH0alk ₄ , alki, alk, alk ₃ and alk ₄ representing an alkyl radical containing up to 8 carbon atoms, R ₂ represents a hydrogen atom or a halogen atom, R ₃ represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, or a halogen atom, R ₄ represents an NHR 'or NHOR''radical in which R' or R '' identical or different represent a hydrogen atom, a radical alkyl, alkeny the linear or branched or cyclic or alkynyl containing up to 8 carbon atoms, an aryl radical containing up to 14 optionally substituted carbon atoms, R ₅ represents a hydrogen atom or an O-alkyl radical containing up to 8 carbon atoms,

R ₆ an alkyl radical or CH ₂ -0 -alkyl, in which alkyl represents an alkyl radical containing up to 8 atoms carbon,

2) The compounds of formula (I) defined in claim 1 in which RI represents an alkyl radical containing up to 4 carbon atoms.

3) The compounds of formula (I) defined in claim 2 in which R represents a radical:

4) The compounds of formula (I) defined in claim 1 in which Ri represents a benzoyl radical.

5) The compounds of formula (I) defined in any one of claims 1 to 4 in which R ₂ represents a hydrogen atom. 6) The compounds of formula (I) defined in one of claims 1 to 5 in which R ₃ represents a methyl radical.

7) The compounds of formula (I) defined in one of claims 1 to 6 in which R ₅ is an OCH ₃ radical. 8) the compounds of formula (I) defined in any one of claims 1 to 7 in which R ₆ and R ₇ represent a methyl radical.

9) The compounds of formula (I) defined in any one of claims 1 to 7 in which R ₆ and R ₇ represent an ethyl radical.

10) The compounds of formula (I) defined in any one of claims 1 to 7 in which R _G and R ₇ form with the carbons which carry them a cyclopentyl radical.

11) The compounds of formula (I) defined in any one of claims 1 to 7 in which R ₄ represents an NH-O-CH ₂ -C≡CH radical.

12) The compound of formula (I) defined in claim 1, the name of which follows: - [7R- (7.α., 8 β., 9 β., 10.α)] - (2 -propynyloxy) -carbamate de 8- hydroxy-7- [4 -hydroxy- 8 -methyl -2 -oxo - 3 - (benzoylamino) -2H-1- benzopyran-7-yl] -10-methoxy-6-oxaspiro [4.5] decan-9-yle.

13) The compound of formula (I) defined in claim 1, the name of which follows:

- [7R- (7.α., 8 β., 9 β., 10.α)] - (2 -propynyloxy) -carbamate of 7- [4-hydroxy-8-methyl-3- [(2 -methyl -1-oxo-propyl) amino] -2-oxo-

2H-1-benzopyran-7-yl] -10-methoxy-6-oxaspiro [4.5] decan-9-yl.

14) As medicaments the compounds of formula (I) defined in claim 1 as well as their addition salts with pharmaceutically acceptable acids.

15) As medicaments the compounds of formula (I) defined in claim 12 or 13 as well as their addition salts with pharmaceutically acceptable acids. 16) The pharmaceutical compositions containing as active principle at least one medicament defined in claim 14 or 15.

17) Process for preparing the compounds of formula (I) defined in claim 1, characterized in that a compound of formula (II) is subjected:

to the action of a compound of formula in which R _x retains its previous meaning and Hal represents a halogen atom to obtain the compound of formula (III):

that we submit to the action of a compound of formula

R ₄ H (IV)

to get the compound of formula

18) As new chemicals, the compounds of formula (II) and (III) defined in claim 17.

19) Variant of the method according to claim 17 characterized in that a compound of formula (V) is subjected:

in which the substituents retain their previous meaning and OM represents a blocked hydroxyl radical, to the action of a compound RiCOHal, in which Ri retains its previous meaning and Hal represents a halogen atom, then to the action of a agent for releasing the OH function to obtain the corresponding compound of formula (I)

20) As new chemicals, the compounds of formula (V) defined in claim 19.