Title of Invention

"ERYTHRONOLIDE A DERIVATIVES OF FORMULA (I) AND PROCESS FOR PREPARING THE SAME"

Abstract Eiythronolide A derivatives: in which R represents a carboxylic acid remainder containing up to 18 carbon atoms.
Full Text The present invention relates to erythronolide A derivatives and process for preparing the same.
A subject of the invention is the compounds of formula (I) :
(Formula Removed)
in which R represents a carboxylic acid remainder containing up to 18 carbon atoms.
Among the carboxylic acid remainders, there can in particular be mentioned the acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tert-valeryl and pivalyl radicals.
A more particular subject of the invention is the compounds of formula (I) in which R represents an acetyl radical.
A subject of the invention is also a preparation process characterized in that a compound of formula (II):


0 R in which R retains its previous meaning, is subjected to the
action of an agent capable of selectively activating the hydroxyl in position 11, then to the action of a base to obtain the compound of formula (III):
which is subjected to the action of carbonyldiimidazole, then to the action of the hydrazine NH2NH2 to obtain the corresponding compound of formula (I).
The compounds of formula (II) are known in a general way and can be prepared according to the process described in European Patent Application 619319.
In a preferred implementation,
the agent capable of selectively activating the hydroxyl in position 11 is a sulphonic acid derivative such as methane-sulphonic, paratoluenesulphonic, trifluoromethanesulphonic anhydride or thionyl chloride SOC12, which forms a cyclic sulphite with the OH function in position 12,
- the base used to produce a 10(11) double bond is a
diazabicycloundecene, for example DBU (or 1,8-diazabicyclo-
[5-4-0]undec-7-ene), or DBN (or 1,5-diazabicyclo[4,3,0]non-5-
ene or 2,6-lutidine, or 2,4,6-collidine or tetramethyl-
guanidine,
- the reaction of the compound of formula (III) with
carbonyldiimidazole takes place in the presence of one of the
bases mentioned above or also in the presence of sodium
hydride, triethylamine, sodium or potassium carbonate or
bicarbonate, NaNfSiMe-^^ or LiN(SiMe3)2/
- the hydrazine is used in the form of hydrazine hydrate.
The obtained compounds of formula (III) are new products and are themselves a subject of the present invention.
The subject of the invention is therefore, as chemical products, the compounds of formula (III) and quite particularly the compound of formula (III) in which R represents an acetyl radical.
The compounds of formula (I) are useful intermediate products which can in particular lead to the preparation of antibiotic products, described and claimed in European Patent Application 0,676,409.
In particular, a subject of the invention is the use, characterised in that a compound of formula (I) is subjected to the action of a cleaving agent of the protected hydroxyl functions to obtain the compound of formula (IV):

which is subjected to the action of an aldehyde of formula (V) :
(V)
•C H
n which R'.^ represents a hydrogen atom or a saturated or unsaturated hydrocarbon radical containing up to 23 carbon atoms, optionally interrupted by one or more heteroatoms and optionally having one or more functional groups, to obtain the compound of formula (VI) :


which is subjected to the action of an oxidizing agent of the
hydroxyl in position 3 then to the action of a cleaving agent of the hydroxyl in position 2' to obtain the compound of formula (VII):

0
which is subjected to the action of a reducing agent to obtain the corresponding compound of formula (VIII):

in which R^ retains its previous meaning.
In a preferred implementation, - R'-L represents the radical
(Formula Removed)

- cleavage of the protected hydroxyl functions is carried out
toy saponification then acidification of the ester function,
esterification of the hydroxyl function in position 2 * is carried out according to standard processes,
- oxidation of the hydroxyl in position 3 is carried out
using a diimide in the presence of DMSO, for example the
hydrochloride of 1-ethyl 3-(3-dimethylamino propyl)
carbodiimide,
cleavage of the hydroxyl in position 2' takes place toy methanolysis,
the reducing agent is NaBH3CN or NaBH(OAc)3 or also NaBH4 in the presence of acetic acid or hydrogen in the presence of a catalyst such as palladium, platinum and optionally ±n the presence of an acid such as hydrochloric acid or acetic acid. The products of formula (VII) are products having useful intibiotic properties, described and claimed in European Patent 0,676,409.
Erythronolide A derivatives of formula (I):

(Formula Removed)
in which R represents a carboxylic acid remainder containing up to 18 cartoon atoms.
EXAMPLE1 : 2',3-diaoetate of 11, 12 - dideoxy- 3 -de {2 , 6 - dideoxy-
3-C-methyl-3-0-mathyl-alpha-L-riboh«xopyranosyl)-11,12-
(hydrazono(carbonyloxy))-6-O-mathyl erythromyoin
STAGE A: 2',3-diacetate of ll-deoxy-10,ll-didehydro-3-
de (2,6 -dideoxy- 3 - C-methyl - 3 - O-methyl - alpha- L.- ribohexo-pyranosyl) - 6 -O-methyl- erythromycin
A solution containing 9.45 g of 2',3-diacetate of 3-de-
(2,6-dideoxy-3 -C-methyl- 3-O-methyl-alpha-L-ritoohexo-pyranosyl)- 6 -O-methyl- erythromycin and 112 ml of pyridine is maintained under agitation at 0"C for 15 minutes. 1.52 ml of thionyl chloride is added over 10 minutes. Agitation is continued overnight at ambient temperature. Separation and drying are carried out. The resultant product is poured into a mixture of 150 ml of ethyl acetate and 200 ml of sodium bicarbonate. Agitation is carried out for 10 minutes.

Decantation is carried out, then extraction with ethyl acetate and drying. 10.7 g of product is obtained.
A mixture of 10.7 g of this product and 124 ml of dimethyl-formamide is agitated at 50°C. 2.53 ml of DBU is added over 5 minutes. Agitation is carried out for 48 hours at 50°C, and the mixture is then poured into water. 100 cm3 of ethyl acetate is added. Decantation is carried out, and the resultant product is washed with water (1.25 1), extracted with ethyl acetate (400 ml) and dried over magnesium sulphate, then filtered and the filtrate is evaporated to dryness. Approximately 50 ml of isopropyl ether is added, and the mixture is left to crystallize for 72 hours, filtered, rinsed and dried. 5.514 g of desired product, which melts at 174°C, is obtained.
STAGE B; 2',3-diacetate of 11,12-dideoxy-3-de(2,6-dideoxy-3 -C-methyl- 3 -0-methyl-alpha-L-ribohexopyranosy1)-11,12-(hydrazono(carbonyloxy))-6-0-methyl erythromicin
A mixture containing 2.623 g of product prepared in the
preceding stage, 972 mg of carbonyldiimidazole, 30 ml of
dichloromethane and 60 ^il of DBU is agitated. Agitation is
maintained for 4 hours. 404 /zl of hydrazine hydrate is
added. Agitation is carried out for 24 hours, and 50 ml of
0.5 M sodium acid phosphate is added. The mixture is decanted
and the resultant product is extracted with methylene
chloride and dried. The product is taken up in isopropyl
ether. The mixture is left to crystallize overnight.
Filtration, rinsing with isopropyl ether and drying are
carried out. 2.415 g of desired product is obtained.
NMR CDC13 ppm
0.84 (t) CH^-CH,
J £*
1.00 (d) 1.10 (d)
1.12 (d) - 1.15 (d) CH-Me's
1.23 (d)
1.28 (s) 6 and 12 Me
1.40 (s)
2.09 (s) OAc's
2.18 (s)
2.26 (s) NMe2

2.61 (m) (2H) H8 and H'3
2.88 (m) H2
s 3.06 (m) H1Q
3.2 (s) C-OMe
3.33 (m) H'5
3.67 (s) HX1
3.69 (d) H5
4.2 (d) H^ax
4.53 (bs) (2H) NH2
4.73 (dd) H'^ax
£*
5.03 (d) H3
5.13 (dd) H13
USE; 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0- methyl-alpha-L-ribohexopyranosyl)oxy) 6-0-methyl 3-oxo 12,ll-(oxy-carbonyl) (2 - (3 - (4-quinoleinyl) 2 -propyl) hydrazono)) ery thromy c in
STAGE A: 11,12-dideoxy-3 -de(2,6-dideoxy-3 -C-methyl-3-0-methy1-alpha-L-ribohexopyranosyl) 11,12-(hydrazono (carbonyloxy)) 6-0-methyl erythromycin
A mixture containing 714 mg of product from Example 1 Stage B, 7.5 ml of isopropanol and 2 ml of N soda is agitated for 30 minutes. The reaction mixture is maintained at ambient temperature for 48 hours. 2 ml of a normal hydrochloric acid solution is added. The mixture is evaporated to dryness. The product obtained is chromatographed on silica, eluting with an ethyl acetate-triethylamine (9-1) mixture. 300 mg of desired product is obtained.
STAGE B: 2'-acetate of 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) 12,11-(oxy-carbonyl) (3-(4-quinolinyl) propylidene) hydrazono) 6-0-methyl erythromycin
281 ml of 4-quinolinylpropanaldehyde, 10.2 ml of toluene, 802 mg of product prepared in the preceding stage and 306 ^1 of acetic acid are maintained under agitation and a nitrogen atmosphere for 4 hours. The mixture is evaporated to dryness. The product obtained is chromatographed on silica, eluting with an ethyl acetate-triethylamine (95-5)

mixture, then with an ethyl acetate-triethylamine (90-10) mixture. 916 mg of the product is obtained.
839 mg of this product, 10 ml of methylene chloride and 121 [il of acetic anhydride are maintained under agitation overnight. 8.55 ml of ammonia water is added. Agitation is carried out for 10 minutes, the product is extracted with methylene chloride and dried. 846 mg of desired product is obtained.
STAGE C: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyloxy)3-oxo 12,11-(oxycarbonyl (3-(4-quinolinyl) propylidene) hydrazono)) 6-0-methyl erythromycin
A mixture containing 1.783 g of 1-ethyl 3-(3-dimethyl-amino propylcarbodiimide) hydrochloride, 1.67 ml of DMSO and 11 ml of methylene chloride is agitated for 15 minutes. 781 mg of product prepared in the preceding stage and 8 ml of methylene chloride are added. The mixture is maintained under agitation for 1.30 hours and 1.8 g de pyridinium trifluoroacetate is added. Agitation is carried out for 3 hours at ambient temperature, and 30 ml of ammonium hydroxide is added. Agitation is maintained for 15 minutes, extraction with methylene chloride and drying over magnesium sulphate are carried out. The product is chromatographed on silica, eluting with an ethyl acetate-triethylamine (9-1) mixture. 647 mg of product is collected. A mixture of 566 mg of this product and 18 ml of methanol is maintained under agitation overnight and 540 mg of desired product is obtained. STAGE D; 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11 (oxycarbonyl (2-(3-(4-quinoleinyl) 2-propyl) hydrazono)) erythromycin
0.38 g of product prepared in the preceding stage and 38 mg of platinum oxide are dissolved in 10 ml of ethyl acetate. Hydrogenation is carried out for 24 hours under vigourous agitation. The mixture is filtered, rinsed with ethyl acetate and evaporated under reduced pressure. 0.375 g of product is obtained, which is taken up in 5 ml of methanol, 175 /xl of acetic acid and 90 mg of sodium
borohydride. Agitation is carried out for 3 hours at ambient
temperature. The methanol is driven off and the product is
taken up in a methylene chloride-water mixture. The pH is
adjusted to 8-9 with a 28% ammonium hydroxide solution.
Decantation is carried out, the product is washed with water,
dried, filtered and evaporated to dryness. 0.37 g of product
is obtained, which is chromatographed on silica, eluting with
an ethyl acetate- triethylamine 96-4 mixture. 127 mg of a
product (rf = 0.25) is obtained which is separated off,
washed and dried. 90 mg of the desired product M.p. = 189°C
is obtained.
NMR CDC13 ppm, 300 MHz
1.34 (s)-1.48 (s) : 6 and 12 CH3; 2.30 (s): N(CH3)2;
2.65 (s): 6-OCH3; 3.06 (dq): H4; 3.19 (q): H1Q; 3.74 (s):
Hllf- 5.50 (mobile t.): NH-CH2; 7.30 (d) : H3 quinoline; 7.53-
7.68 (dt): H6-H7 quinoline; 8.10 (m):
H5-H8 quinoline; 8.79 (d): H2 quinoline.






We claim:
1. Erythronolide A derivatives of formula (I):

(Formula Removed)
in which R represents a carboxylic acid remainder containing up to 18 carbon atoms.
2. The derivatives of formula (I) as claimed in claim 1, in which R represents an acetyl radical.
3. Preparation process for the compounds of formula (I) as defined in claim 1 or 2, wherein a compound of formula (II):

(Formula Removed)

in which R retains its previous meaning, is. subjected to the action of an agent capable of selectively activating the hydroxyl in position 11, then to the action of a base to
obtain the compound of formula (III):

(Formula Removed)
which is subjected to the action of carbonyldiimidazole, then to the action of the hydrazine NH2NH2 to obtain the corresponding compound of formula (I).
4. Derivatives of formula I substantially as herein described with reference to the foregoing examples.

5. A process of preparing a compound of formula I substantially as herein described with reference to the foregoing examples.

Documents:

1771-DEL-1996-Abstract-(16-09-2008).pdf

1771-DEL-1996-Abstract-(27-08-2008).pdf

1771-DEL-1996-Abstract-12-05-2008.pdf

1771-del-1996-abstract.pdf

1771-DEL-1996-Claims-(27-08-2008).pdf

1771-DEL-1996-Claims-12-05-2008.pdf

1771-del-1996-claims.pdf

1771-DEL-1996-Correspondence-Others-(27-08-2008).pdf

1771-DEL-1996-Correspondence-Others-12-05-2008.pdf

1771-del-1996-correspondence-others.pdf

1771-DEL-1996-Description (Complete)-(16-09-2008).pdf

1771-del-1996-description (complete)-12-05-2008.pdf

1771-del-1996-description (complete)-27-08-2008.pdf

1771-del-1996-description (complete).pdf

1771-DEL-1996-Form-1-(16-09-2008).pdf

1771-DEL-1996-Form-1-(27-08-2008).pdf

1771-DEL-1996-Form-1-12-05-2008.pdf

1771-del-1996-form-1.pdf

1771-del-1996-form-10.pdf

1771-del-1996-form-18.pdf

1771-DEL-1996-Form-2-(16-09-2008).pdf

1771-DEL-1996-Form-2-(27-08-2008).pdf

1771-DEL-1996-Form-2-12-05-2008.pdf

1771-del-1996-form-2.pdf

1771-DEL-1996-Form-3-12-05-2008.pdf

1771-del-1996-form-4.pdf

1771-del-1996-form-6.pdf

1771-DEL-1996-GPA-12-05-2008.pdf

1771-del-1996-gpa.pdf

1771-DEL-1996-Petition-137-12-05-2008.pdf

1771-DEL-1996-Petition-138-12-05-2008.pdf

abstract.jpg


Patent Number 224581
Indian Patent Application Number 1771/DEL/1996
PG Journal Number 44/2008
Publication Date 31-Oct-2008
Grant Date 20-Oct-2008
Date of Filing 09-Aug-1996
Name of Patentee AVENTIS PHARMA S.A.
Applicant Address 20 AVENUE RAYMOND-ARON, F-92160 ANTONY, FRANCE.
Inventors:
# Inventor's Name Inventor's Address
1 NA 19, RUE ROBERT SCHUMAN, F-93410 VAUJOURS, FRANCE
2 ALAIN BONNET D-56 LA BUISSONNIERE, 3, RUE FERDINAND BUISSON, F-77100 MEAUX, FRANCE.
3 BERNADETTE CHAPPERT 42 BIS, RUE PLANCHAT, F-75020 PARIS, FRANCE
4 JACQUES LAGOUARDAT 21, CLOS DES CASCADES, F-93160 NOISY LE GRAND, FRANCE
PCT International Classification Number C07D 313/04
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 95 11861 1995-10-09 France