Title of Invention

"2-FLUORO-3DE((2,6-DIDEOXY-3-C-METHYL-3-O-METHYL-ALPHA-L-RIBO-HEOSPYRANOSYL)OXY) 6-O-METHYL-3-OXO-ERYTHROMYCIN COMPOUND OF FORMULA (I)"

Abstract

A subject of the invention is the compounds of formula in which either A represents an OH radical and B forms with the carbon in position 10 a carbon-carbon double bond, or A and B together form a carbonate or carbamate and OZ represents a free, esterified or etherified hydroxyl radical, as well as their addition salts with acids. The products of formula (I) are used in the synthesis of medicaments.

Full Text

New derivatives of 2-fluoro 3-de[(2,6-dideoxy 3-C-methyl 3-O-methyl-a-L-ribohexopyranosyl) oxy] 6-O-methyl 3-oxo erythromycin, their preparation process and their use for the synthesis of the active ingredients of medicaments. The present invention relates to new derivatives of 2-fluoro 3-de((2,6-dideoxy-3-C-methyl-3-0-methyl-a-L-ribo-hexopyrasonyl) oxy) 6-O-methyl 3-oxo erythromycin, their preparation process and their use for the synthesis of the active ingredients of medicaments. A subject of the invention is the compounds of formula (I) : (Figure Removed) in which either A represents an OH radical and B forms with the carbon in position 10 a carbon-carbon double bond, or A and B together form a carbonate or carbamate and OZ represents a free, esterified or etherified hydroxyl radical, as well as their addition salts with acids. Among the addition salts with acids, the salts formed with the following acids can be mentioned: hydrofluoric, hydrochloric, hydrobromic, hydroiodic, acetic, propionic, trifluoroacet....c, maleic, tartaric, methanesulphonic, benzenesuiphonic, p-toluenesulphonic, and especially stearic, ethylsuccinic or laurylsuccinic acids. In particular a subject of the invention is the compounds of formula (I), in which Z represents a hydrogen atom, those in which Z represents a COCHs radical and those in which Z represents a trimethylsilyl radical. Among the preferred compounds of the invention, there can be mentioned the compounds corresponding to formula (IA) : (Figure Removed) in which Z regains its previous meaning, and those corresponding to formula (IB) : (Figure Removed) in which Z retains its previous meaning. Naturally a quite particular subject of the invention is the compounds of formula (I) the preparation of which is given hereafter in the experimental part. A subject of the invention is also a preparation process, characterized in that a compound of formula (A) : (Figure Removed) is subjected to the action of a fluoridation agent in order to obtain the corresponding compound of formula (I), then if desired the nydroxyl in position 2' is released, the hydroxyl in position 2' is esterified or etherified, and/or if desired the compound of formula (I) in which A and B form a carbonate radical (IB) is subjected to the action of a strong base in order to obtain the compound of formula (IA) which if desired is subjected to the action of an acid in order to form the salt. As fluoridation agent, the N-fluoro-Bis (phenylsulphonyl) imide can be mentioned of formula : (Figure Removed) but also any electrophilic fluoridation agents. As an agent for releasing the hydroxyl in position 2', there can be mentioned strong bases such as tetrabutyl-ammonium fluoride when OZ is an OSi(CH3)3 group or alcohols such as methanol when OZ is a COCH3 radical. The compounds of formula (I) are used for the preparation of medicaments; in particular they allow the preparation of the products of European Patent 799833. In part-cular a subject of the invention is the use of products of formula (I), characterized in that a compound of formula (I), is subjected to the action of carbonyl-diimidazoLe ._n order to obtain the compound of formula (II) : (Figure Removed) which is subjected to the action of an amine H2NR in order to obtain the compound of formula (III) : (Figure Removed) then if desired the hydroxyl in position 2' is released. The experimental part gives a detailed example of the use of compounds of formula (I). A subject of the invention is also the compounds of formula (II) defined above as new chemical products and in particular 12-(oxycarbonylimidazol) 11-deoxy 10,11-didehydro 3-de[(2,6-dideoxy 3-C-methyl 3-0-methyl a-L-ribohexopyranosyl) oxy] 6-0-methyl 3-oxo erythromycin 2'-acetoxy 2a-fluoro. The folLowing examples illustrate the invention without however limiting it. EXAMPLE 1: 3-de[(2,6-dideoxy 3-C-methyl 3-O-methyl a-L-ribohexopyranosyl) oxy] 6-O-iaethyl 3-oxo erythromycin cyclic 2'-trimethylsilyloxy 2a-fluoro 11,12-carbonate. 1.27 ml of a solution 1M of potassium terbutylate in THF in is added at -78°C to a solution containing 685 mg of 3-de-[(2,6-dideoxy 3-c-methyl 3-0-methyl a-L-ribohexopyranosyl) oxy! 6-0-methyl 3-oxo erythromycin cyclic 2'- trimethylsilyloxy 11,12-carbonate and 10 ml of anhydrous THF. Agitation is carried out for 5 minutes at -78°C and 389 mg of N-fluoro-benzene sulphonimide is added. The reaction medium is maintained at -78°C for 3 hours, followed by evaporation and 5 ml of ethyl acetate, 5 ml of water and 0.5 ml of concentrated ammonium hydroxide are added. The reaction medium is maintained at ambient temperature for 10 minutes, decanted, the organic phase is washed with water, followed by drying and evaporating. NMR 250 MHz CDC13: H13 (dd) : 4.80; NMe2 (s): 2.11; CH3-C-F (d) : 1.65 J=22 Hz; SiMe3 (s): 0.02. Preparation of the starting product of Example 1. 6.14 g of 3-de- [ (2, 6-dideoxy 3-C-methyl 3-0-methyl-a-oxy] 6-O-methyl 3-oxo erythromycin cyclic 11,12-carbonate, 660 mg of imidazole, 62 ml of anhydrous THF and 2.05 ml of hexamethyl-disilylazane are agitated at ambient temperature for 4 days, followed by evaporating and taking up with methylene chloride and sodium acid phosphate. Agitation is carried out for 15 minutes, followed by decanting, extraction with methylene chloride, drying and evaporating. 5.02 g of sought product is obtained. NMR 250 MHz CDC13: H13 (dd) : 4.80; 6-OMe: 2.51 (s), NMe2: 2.11 (s); SiMe3: 0.05. EXAMPLE 2: 11-deoxy 10,11-didehydro 3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl a-L-ribohexopyranosyl) oxy] 6-O-methyl 3-oxo erythromycin 2'-trimethylsilyloxy 2a-fluoro. 1.24 ml of a solution of potassium terbutylate in 0.97M THF is added at -12°C to a solution containing 668 mg of 11-deoxy 10,11-didehydro 3-de[(2, 6-dideoxy-3-C-methyl-3-0-methyl a-L-ribohexopyrasonyl) oxy] 6-O-methyl 3-oxo erythromycin 2'-trimethylsilyloxy and 6.7 ml of anhydrous THF. Agitation is carried out for 5 minutes and 378 mg of N-fluoro dibenzenesulphonimide is added. Agitation is carried out for 10 minutes at -12°C and the reaction medium is left to return to ambient temperature for 1 hour 30 minutes. Isolation and purification operations are carried out and 695 mg of sought product is obtained. NMR 250 MHz CDC13: Hu (s): 6.42; Hi3 (dd) : 4.85; 6-OMe: 2.55 (s), N(Me)2: 2.12 (s); CH.3-C-F (d) : 1.60 J = 22Hz. Preparation of the starting product of Example 2. Stac[e__A: 11-deoxy 10 , 11-didehydro 3-de [ (2 , 6-dideoxy-3-C-methyl 3-0-rnethyl a-L-ribohexopyranosyl) oxy] 6-O-methyl 3-oxo erythromycin. A mixture of 8.722 g of 11-deoxy 10,11-didehydro 3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl a-L-ribohexopyranosyl) oxy] 6-0-methyl 3~oxo erythromycin 2'-acetoxy (EP 596802) and 350 ml of anhydrous methanol are agitated for 44 hours, followed by evaporating, taking up in methylene chloride, drying and 8.794 g of sought product is obtained. NMR 250 MHz CDC13: Hu (s): 6.64; H13 (dd) : 4.99; H'i: 4.25 (d); 6-OMe (s): 2.87, 10 Me (s): 1.96 (s); N(Me)2 (s): 2.25. Stage B: 11-deoxy 10,11-didehydro 3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl a-L-ribohexopyranosyl) oxy] 6-0-methyl 3-oxo erythromycin 2'-trimethylsilyloxy. A mixture containing 3.08 g of the product of the preceding stage, 340 mg of imidazole, 32 ml of anhydrous THF and 1.06 ml of hexamethyldisilylazane is agitated for 4 days at ambient temperature, followed by evaporating to dryness, taking up in a mixture of 60 ml of methylene chloride and 60 ml of 0.5M sodium acid phosphate. The reaction mixture is maintained under agitation for 15 minutes, followed by decanting, extracting with methylene chloride, drying and evaporating to dryness. 3.345 g of sought product is obtained. NMR 250 MHz CDC13: H-u: 6.61 (s); Hi3 (dd) : 4.92; 60Me (s): 2.85; N(Me)2: 2.15 (s): SiMe3 (s): 0.02. EXAMPLE 3: 11-deoxy 10,11-didehydro 3-de[(2,6-dideoxy 3-C-methyl 3-O-methyl a-L-ribohexopyrasonyl) oxy] 6-O-methyl 3-oxo erythromycin 2'-acetoxy 2a-fluoro. 2.5 ml of a solution of potassium terbutylate in THF (0,97M) is added at -8°C to a suspension containing 1.224 g of il-deoxy 10,11-didehydro 3-de[(2,6-dideoxy 3-C-methyl 3-O-methyl a-L-ribohexopyranosyl) oxy] 6-0-methyl 3-oxo erythromycin 2'-acetoxy (EP 596802) and 10 ml of anhydrous THF. 756 mg of N-fluorodibenzene-sulphonimide is added. Agitation is carried out for 1 hour at -5°C then 10 ml of saturated bicarbonated water and 10 ml of ethyl acetate are added, agitation is carried out for 10 minutes at ambient temperature, followed by filtering, rinsing, decanting, washing with water, reextracting with ethyl acetate, washing, drying and filtering. Chromatography on silica is carried out eluting with a methylene chloride-methanol mixture with 8% concentrated ammonium hydroxide 95-5. 623 mg of sought product is obtained. NMR: Hn: 6.47 (s); Hi3: 5.03 (dd) ; 6-OMe: 2.66 (s); N-Me2: 2.25 (s): CHj-C-F: 1.75 (d) J = 21.5 Hz. Use of 11,12-dideoxy 3-de[(2,6-dideoxy 3-C-methyl 3-O-methyl-a-L-ribohexopyrasonyl) oxy] 2 Stage A: 11-deoxy 10,11-didehydro 3-def(2,6-dideoxy 3-C-methyl 3-0-methyl a-L-ribohexopyranosyl) oxy] 6-O-methyl 3-oxo erythromycin 2a-fluoro. A mixture of 5.476 g of the product of Example 2, 50 ml of THF and 1L.2 ml of 1M tetrabutylammonium fluoride in THF is agitated for 3 hours 30 minutes. The solvent is evaporated off and 37 ml ethyl acetate, 37 ml of water and 7.5 ml of 20% ammonium hydroxide are added. Agitation is carried out for 10 minutes, followed by decanting, extracting with ethyl acetate, drying, filtering and the filtrate is concentrated to dryness. The product obtained is chromatographed on silica eluting with a CH2Cl2-MeOH ammonium hydroxide mixture 99-1, then 98-2, 97-3, 96-4, 95-5. 2.452 g of sought product is obtained. Stage B: 11-deoxy 10,11-didehydro 3-de[(2,6-dideoxy 3-0-methyl ct-L-r ibohexopyrasonyl) oxy] 6-O-methyl 3-oxo erythromycin 2'-acetoxy 2a-fluoro. 1.02 g of the product of Stage A, 10 ml of methylene chloride and 241 (j.1 of acetic anhydride are maintained under agitation for 3 hours. After evaporation, 10 ml of water and 10 ml of ethyl acetate are added. The reaction medium is left for 1 hour at ambient temperature under agitation, followed by decanting, drying and evaporating. 1.01 g of sought product is obtained. TLC Si02 dichloromethane 95 - MeOH 5 ammonium hydroxide, rf: 0. 14 . NMR 250 MHz :;DC13: HU (s): 6.47; H'2 (q): 4.75; N(Me)2 (s): 2.22; CH3-CO-0 (s): 2.05; CH3-C-F (d): 1.75; J = 22 Hz. C: 12-(oxycarbonylimidazol) 11-deoxy 10,11-didehydro 3- de[(2,6-dideoxy 3-C-methyl 3-0-methyl a-L-ribohexopyranosyl) oxy] 6-0-methyl 3-oxo erythromycin 2'-acetoxy 2a-fluoro. 0.388 g of carbonyldiimidazole and 24 (J.1 of DBU are added at 0°C to a solution containing 1.01 g of the product of the preceding stage and 10 ml of anhydrous THF. The THF is evaporated off and 10 ml of water and 10 ml of ethyl acetate are added. The reaction mixture is maintained under agitation for 10 minutes, followed by extracting, drying and evaporating. 0.902 g of crude sought product is obtained which is chromatographed eluting with an ethyl acetate -triethylamine mixture 96-4, 0.573 g of sought product is obtained. NMR (CDC13) : Hlt: 6.69 (s) ; H13: 5.55 (dd) ; 6-OMe: 2.62 (s); N-Me2: 2.25 (s): 10-Me: 1.90 (s). Stage D: 2'-acetoxy 11,12-dideoxy 3-de[(2,6-dideoxy 3-C-methyl 3-0-methyl a-L-ribohexopyrasonyl) oxy] 2a-fluoro 6-0-methyl 3-oxo 12,11-[oxycarbonyl [4-[4-(3-pyridinyl) 1H-imidazol-1-yl] butyl] imino] erythromycin A. 211 mg of 4-(3-pyridinyl) IH-imidazol-l-butylamine, 573 mg of the product of the preceding stage and 5 ml of anhydrous TH? are added together at 0°C. 19 jal of DBU is added. The reaction mixture is kept in a refrigerator overnight. After evaporation, 10 ml of ethyl acetate and 10 ml of water are added. Agitation is carried out for 10 minutes , followed by extracting, drying and evaporating. 0.545 g of crude sought product is obtained which is used as it is for the following stage. Stage E: 11, L2-dideoxy 3-de [(2, 6-dideoxy 3-Omethyl 3-0-methyl-a-L-rLbohexopyranosyl) oxy] 2a-fluoro 6-0-methyl 3-oxo 12,11-[oxycarbonyl [4-[4-(3-pyridinyl) IH-imidazol-l-yl] butyl] iminoi erythromycin A. The preceding product is taken up in methanol. The reaction mixture is maintained under agitation at ambient temperature for 24 hours. The product obtained is chromatographed on silica eluting with an ethyl acetate -triethylamine mixture 96-4. After evaporation, 189 mg of sought product is obtained. WE CLAIM: 1) 2-Fluoro-3-de((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo- hexopyranosyl)oxy)6-0-methyl-3-oxo-erythromycin compound of formula (I): (Formula Removed) wherein either A represents an OH radical and B forms with the carbon in position 10 a carbon-carbon double bond, or A and B together form a carbonate or carbamate and OZ represents a free, esterified or etherifid hydroxyl radical, as well as their addition salts with acids. 2. The compound of formula (I) as claimed in claim 1, wherein Z represents a hydrogen atom, COCH3 radical or trimethylsilyl radical. 3. The compound of formula (I) as claimed in any one of claims 1 and 2, corresponding to formula (IA): (Formula Removed) wherein Z retains its previous meaning. 4. The compound of formula (I) as claimed in any one of claims 1 to 4, corresponding to formula (IB): (Formula Removed) wherein z retains its previous meaning. 5. Preparation process for the compound of formula (I) as claimed in claim 1, wherein a compound of formula (A): (Formula Removed) is subjected to the action of a fluoridation agent in order to obtain the corresponding compound of formula (I), then optionally the hydroxyl in position 2' is released, the hydroxyl in position 2' is esterified or etherified, and/or optionally the compound of formula (I) wherein A and B form a carbonate radical (IB) is subjected to the action of a strong base in order to obtain the compound of formula (IA) which if desired is subjected to the action of an acid in order to form the salt. 6. The compound of formula I substantially as hereinbefore described with reference to the foregoing examples.

Documents:

0374-del-1999-abstract.pdf

0374-del-1999-claims.pdf

0374-del-1999-correspondence-others.pdf

0374-del-1999-description (complete).pdf

0374-del-1999-form-1.pdf

0374-del-1999-form-18.pdf

0374-del-1999-form-2.pdf

0374-del-1999-form-4.pdf

0374-del-1999-form-6.pdf

0374-del-1999-gpa.pdf

374-DEL-1999-Abstract (15-11-2007).pdf

374-DEL-1999-Claims (15-11-2007).pdf

374-DEL-1999-Correspondence-Others.pdf

374-DEL-1999-Description (Complete) (15-11-2007).pdf

374-DEL-1999-Form-1(15-11-2007).pdf

374-DEL-1999-Form-13(15-11-2007).pdf

374-DEL-1999-Form-2(15-11-2007).pdf

374-DEL-1999-Form-3(15-11-2007).pdf

374-DEL-1999-Form-5(15-11-2007).pdf

374-DEL-1999-GPA(15-11-2007).pdf

374-DEL-1999-Others-Documents(15-11-2007).pdf

374-DEL-1999-Petition-137(15-11-2007).pdf