AP887A - Novel 5-0-deoaminyl 6-0-methyl erythronolide a derivatives method for preparing same application thereof for preparing biologically active products. - Google Patents
Novel 5-0-deoaminyl 6-0-methyl erythronolide a derivatives method for preparing same application thereof for preparing biologically active products. Download PDFInfo
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- AP887A AP887A APAP/P/1998/001210A AP9801210A AP887A AP 887 A AP887 A AP 887A AP 9801210 A AP9801210 A AP 9801210A AP 887 A AP887 A AP 887A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
A subject of the invention is the compounds of formula (I): in which OR-| , OR2 and OR3 represent hydroxyl radicals blocked in the form of easily cleavable radicals. The compounds of formula (I) can be used to prepare antibiotic products.
Description
New derivatives of 5-O-desosaminyl 6-O-methyl erythronolide A, their preparation process and their use for the preparation of bioloqically-active products.
The present invention relates to new derivatives of 5-Odesosaminyl 6-O-methyl erythronolide A, their preparation process and their use for the preparation of biologicallyactive products.
A subject of the invention is the compounds of formula (I) :
(I)
AP/P/ 98/01210
(..·· in which:
either Rq represents an alkyl radical containing up to 8 carbon atoms substituted by one or more alkyl radicals containing up to 8 carbon atoms, or by one or more aryl radicals containing up to 14 carbon atoms, or Rq represents an aryl radical containing up to 14 carbon atoms, optionally substituted by one or more alkyl, alkenyl or alkynyl radicals containing up to 8 carbon atoms, alkoxy or alkylthio radicals containing up to 8 carbon atoms, nitro, CF3 radicals or by one or more halogen atoms, or Rq represents a radical:
Rb·
Ra
I
-CRc
APO 0 0 8 8 7
- 2 in which Ra represents an alkyl or alkoxy radical containing up to 8 carbon atoms,
Rb represents an alkyl radical containing up to 8 carbon atoms, optionally substituted by a heteroatom,
Rc represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms,
R2 and R3, identical or different, represent a trialkylsilyl radical in which the alkyl radical contains up to 8 carbon atoms,
R' a
I a -C--R'b radical, a C- Rd radical,
R'c ΰ in which R'a, R'b, R'c and Rd represent an alkyl radical containing up to 8 carbon atoms, or an aralkyl radical containing up to 8 carbon atoms, optionally substituted by one or or more of the substituents indicated above for Rq.
/In the definition of compounds of the invention:
- the alkyl, alkenyl or alkynyl radical is preferably one of the following radicals: methyl, ethyl, propyl, isopropyl, nbutyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl,
- the halogen is preferably fluorine or chlorine, or bromine,
- the aryl radical is preferably the phenyl radical, or a naphthyl radical,
- the aralkyl radical is preferably a (C5H5)-(CH2)a radical, a being an integer comprised between 1 and 6, for example the number 1, 2, 3 or 4; the aralkyl radical can be for example, an optionally substituted benzyl radical or a trityl radical,
- the alkyloxy radical is preferably one of the following radicals: methoxy, ethoxy, propyloxy isopropyloxy, nbutyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, sec-pentyloxy, tert-pentyloxy, neopentyloxy, nhexyloxy, sec-hexyloxy, tert-hexyloxy,
- the corresponding alkylthio radical can be used by taking the same values and replacing the oxygen atom with a sulphur, atom, for example: methylthio, ethylthio. Furthermore, the sulphur atom -can be oxidized, for example: methylsulphinyl,
AP/P/ 98/01210
APO00887
- 3 methyisulphonyl.
The compounds of the invention can be used for the preparation of compounds of formula (VI):
in which Z represents a hydrogen atom or a protective group such as the remainder of a carboxylic acid containing up to 8 carbon atoms, a trialkylsilyl or terbutyl radical. The compounds of formula (VI) are described and claimed in the , *
European Patent Application 0,487,411, as intermediates useful in particular for the preparation of antibiotic products.
A more particular subject of the invention is the compounds of formula (I) in which R-] represents a
Ra
Rb-0-CRc radical in which Ra, Rb and Rc retain the same meaning as previously and in particular those in which Ra, Rb and Rc represent a methyl radical as well as the compounds of formula (I) in which R2 and R3 both represent a trialkylsilyl
AP/P/ 9 8/01210
APO 00 8 8 7
- 4 radical and in particular those in which F?2 and R3 represent a trimethylsilyl radical.
A more particular subject of the invention is the compound of formula (I) whose preparation is given hereafter in the experimental part.
A subject of the invention is also a preparation process for the compounds of formula (I) as defined previously, characterized in that the compound of formula (II):
is subjected to the action of an agent blocking the oxime in position 9, in order to obtain a compound of formula (III):
H
AP/P/ 9 8/01210 in which R-| retains its previous meaning, which is subjected to the action of an agent blocking the hydroxyl in position 3 and/or in position 2' in order to obtain the compound of formula (IV):
ΑΡΟ 00687
- 5 \~ϊ·
in which R-j , R2 and R3 retain their previous meaning, which is subjected to the action of a methylation agent of the hydroxyl in position 6, in order to obtain the corresponding compound of formula (I).
The compound of formula (II) used as starting product is a known product described by Le Mahieu et al. in J. Med.
Chem. 1_7 (9) 953-956 (1974).
In a preferred implementation of the process of the invention:
- the oxime in position 9 is protected in the ketal or thioketal form,
- the 3-OH and 2'-OH groups are blocked by trimethylsilyl groups,
- the methylation is carried out using methyl iodide in the presence of a base for example potash, soda, a hydride such as sodium hydride, an alkali metal terbutylate such as for example potassium terbutylate or also in the presence of 1,5diazabicyclo [4,3,0] non-5-ene or 1,8-diazabicyclo [5,4,0] undec-7-ene.
AP/P/ 98/01210
APO00887
- 6 A subject of the invention is also as new chemical products the products of formula (III) and formula (IV) obtained during the implementation of the process of the invention. A more particular subject of the invention is the products of formulae (III) and (IV) whose preparation is given hereafter in the experimental part.
A subject of the invention is also the use of the compounds of formula (I), characterized in that the compound of formula (I) is subject to the following stages:
- release of the oxime in position 9,
- release of the hydroxyl in position 3 and 2',
- protection of the hydroxyl in position 2'.
A particular subject of the invention is the use characterized in that a compound of formula (I) is subjected to the action of formic acid in the presence of sodium bisulphite or sodium metabisulphite in order to directly obtain the compound of formula (V):
AP/P/ 9 8/01210 which is subjected to the action of a protection agent of the hydroxyl in position 2' in order to obtain the compound of formula (VI):
AP Ο Ο Ο 8 8 7
- Ί -
in which Ζ represents a protective group such as the remainder of a carboxylic acid containing up to 8 carbon atoms, or a trialkylsilyl, terbutyl or triphenylmethyl radical.
J
In addition a subject of the invention is the use characterized in that a compound of formula (I) is subjected to the action of an agent releasing the hydroxyl in position 3 and in position 2' in order to obtain the compound of formula (VII):
AP/P/ 98/01210
H in which R-j retains its previous meaning, which is subjected to the action of a protection agent of the OH group in position 2' in order to obtain the compound of formula (VIII):
ΑΡουυβ87
(VIII)
J in which R] retains its previous meaning and Z represents a 20 protective group as defined previously, which is subjected to the action of an agent releasing the 9-oxo group in order to obtain the corresponding compound of formula (VI):
AP/P/ 98/01210 in which Z reutains its previous meaning.
AP Ο ϋ Ο β 8 7
- 9 The following examples illustrate the invention without however limiting it.
EXAMPLE 1: 9—O—(1—methoxy—1—methylethyl) oxime of 3—0— de(2,6—dideoxy—3—C—methyl—3—0—methyl—alpha—L—ribo— hexopyranosyl)-2',3-0—bis (trimethylsilyl) 6—0—methyl erythromycin.
Stage A: 9-0-(1-methoxy-1-methylethyl) oxime of 3-0-de(2,6dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) erythromycin
8.14 g of 9-oxime of 3-0-de(2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribo-hexopyranosyl) erythromycin, 81.5 ml of methylene chloride, 9.65 ml of 2-methoxy propene and 2.44 g '/J of 98% pyridinium hydrochloride are agitated for half an hour at ambient temperature. 80 ml of a saturated solution of
NaHC03 added, followed by agitation for 3 minutes. The organic phase is decanted and washed with 50 ml of salt water. The aqueous phases are reextracted with 50 ml of CH2CI2. The organic phase is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 9 g of desired product is recovered.
Yield: 98.5%.
Analytical results:
/ NMR (CDCI3, 300 MHz)
0.84 (t): CH3-CH2; 1.07 (d)-1.09 (d)-1.23 (d)-1.26 (d)x2: the . 3 25 CH3-CH's; 2.25 (s): N(Me)2; 2.48 (m): H'3; 2.64 (dq): H2;
2.72 (bq): H10; 3.22 (s): OMe; -3.25: H'2; 3.51 (d): H5; 3.58 (bd.): H3; 3.68 (bs): Ηη η; -3.50 (m): H'5; -3.62 (m): H8 >
E; 4.41 (d): H'-j; 5.23 (dd): ΗΊ3; 2.36-4.48-3.58: mobile H's.
Stage B: 9-0-(1-methoxy-1-methylethyl) oxime of 3-0-de(2,630 dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl)2' , 3-O-bis(trimethylsilyl) erythromycin
A mixture of 6.62 g of the product prepared in the preceding stage, 66 ml of CH2CI21 2.95 ml of Ntrimethylsilyl imidazole and 1.7 ml of trimethylsilyl chloride is agitated for 45 minutes at ambient temperature.
ml of a saturated solution of NaHC03 is added. The organic phase is decanted and washed with 30 ml of salt water. The aqueous phases are reextracted with 40 ml of
AP/P/ 98/01210
APOϋ0887
- 10 CH2CI2· The organic phase is dried over Na2SC>4 and the solvent is evaporated off under reduced pressure. 7.5 g of desired product is recovered.
Yield: 92.9%.
Analytical results:
NMR (CDCI3, 300 Mhz)
0.12-0.16 the OTMS's; 0.84 (t): CH3-CH7; 1.16 (x2)-1.38-1.451 .47-1.00-1.25: the CH3-CH's; 2.23 (s): N(Me)2,* 2.47 (m):
H'3; 2.71 (m) : H2 and H-|q; 3.16 (dd): H'2; 3.22 (s): OMe;
3.45 (m): H'5; 3.58 (d): H5; 3.66: H8 ---> E; 3.66 (s): Hn ;
3.98 (bd): H3; 4.2 (dd): H'-|; 5.14 (dd): H13; 1.90 (s)-3.104.44: OH.
' Stage C: 9-O-(1-methoxy-1-methylethyl) oxime of 3-O-de(2,6dideoxy-3-C-methyl-3-0-methyl-alpha-L—ribo-hexopyranosyl)15 2',3-O-bis(trimethylsilyl) 6-O-methyl erythromycin
1.24 g of the product prepared in the preceding stage,
8.7 ml of a dimethyl sulphoxide/tetrahydrofuran mixture 1/1, 190 jal of methyl iodide and 161 mg of 90% powdered potash are agitated for 2 hours at ambient temperature. 10 ml of AcOEt and 10 ml of a 0.5 M monosodium phosphate solution are added. After decanting and reextraction with AcOEt, the organic phase is washed with 5 ml of water, dried over Na2SO4 and the filtrate is concentrated under reduced pressure. 1.2 g of the desired product is obtained.
» 25 Yield: 95%.
Analytical results:
NMR (CDCI3, 300 MHz)
Possible structure, the SiMe3's are located at 0.11 and 0.20; 0.84^ (t): CH3-CH2; 0.95 (d)-0.97 (d)-1.14 (d)-1 .17 (d) x 2: the CH3-CH's; 1.18-1.35-1.40-1.48 the CH3-CH's; 2.22 (s): N(Me)2; 2.46 (m): H'3; 2.61 (bq) : H-|0; 2.72 (dg) : H2; 3.01 (s): OMe; 3.13 (dd): H'5; 3.22 (s): OMe chain; 3.45 (m):
H'5; -3.70: H8 ---> E; -3.68 (m): 2H (H3, H5); 3.79 (bs)
1H---> Hn; 4.24 (d): Η'ί; 5.15 (dd): H13; 3.29 (s) and 4.52 the OH's.
Use 1 : 2'—O—acetyl 3—O—de(2,6-dideoxy 3-C—methyl 3—O—methyl alpha—L—ribo—hexopyranosyl) 6-O-methyl erythromycin
Stage A: 3—O-de(2,6-dideoxy 3-C-methyl 3-O-methyl alpha—
01210/86 /d/dV
APO 0 0 887
- 11 ribo-hexopyranosyl) 6-O-methyl erythromycin
A mixture of 513 mg of the product of Example 1, 5 ml of
EtOH/water 1/1, 425 mg of sodium bisulphite and 115 pi of formic acid is agitated under reflux for half an hour. After cooling the mixture down to ambient temperature, 5 ml of a saturated solution of NaHCC>3 is added. The mixture is agitated for 5 minutes then extraction is carried out twice with AcOEt. The extraction phases are washed with 5 ml of a saturated solution of NaCl. The organic phase is dried over
Na2SC>4 and the solvent is evaporated off under vacuum.
180 mg of desired product is obtained, after chromatography k on silica with AcOEt 95/MeOH 3/TEA 2 as eluant.
Yield: 48%.
Analytical results:
NMR (CDCI3, 250 MHz)
Spectrum identical to the data in the literature 5.17 (d): H13; 4.38 (d): H'1; 3.93 (bs): mobile H; 3.85 (s): Hqη; 3.68 (s): H5; 3.54 to 3.62 (m): H3, H's: 3.24 (m): H'2; 2.987 (s): OMe; 2.25 (s): N(Me)2; 1.37-1.31-1.27-1.25-1.2120 1.18-1.14-1.11: theCH3-CH's; 0.83 (t): CH3-CH2·
Stage B: 2'-O-acetyl 3-O-de(2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribo-hexopyranosyl) 6-O-methyl erythromycin 'The product of the preceding stage is subjected to the action of acetic anhydride and the desired product is 1 25 obtained.
Use 2: 2'—O-acetyl 3-O-de(2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribo-hexopyranosyl) 6-O-methyl erythromycin Stage A: 9-0-(2-methoxy 2-methylethyl) oxime of 3-O-de(2,6dideoxy 3qC-methyl 3-O-methyl alpha-L-ribo-hexopyranosyl) 630 0-methyl erythromycin
8.25 ml of 1M tetrabutyl ammonium fluoride in tetrahydrofuran is added rapidly at ambient temperature to a mixture of 2.75 g of the product of Example 1 and 5.5 ml of tetrahydrofuran, then agitation is carried out for 45 minutes. Next a mixture of 15 ml of ethyl acetate and 15 ml of ice-cooled water are added. After decanting, the organic phase is reextracted with 3 ml of water. 0.82 ml of concentrated ammonium hydroxide is added to the aqueous
AP/P/ 9 8/01210 phase? The aqueous phase is extracted with ethyl acetate.
The organic phase is washed with 3 ml of a solution of water saturated with sodium chloride then it is dried over sodium sulphate and the solvent is evaporated off under reduced pressure. 2.17 g of desired product is recovered.
Yield: 95.7%
Analytical results:
NMR (CDCI3, 300 MHz)
AP Ο ϋ Ο 8 8 7
| 0.84 (t): CH3-CH2; | 0.97 | (d) — | 1.10 | (cl)—1 | .18 (d)-1.24 (d)-1. | 26 |
| (d) the CH3-CH's; | 1.20-1 | .40 | (x 2) | -1.48 | the CH3-C's; 2.26 | (s): |
| N(Me)2; 2.13 (bq): | H4; 2 | .48 | (m) : | H'3; | ~2.66: Hqq and H3; | 2.98 |
| (s): OMe in position 6; | 3.22 | (s): | OMe | chain; ~3.26: H'2; | ||
| ~3.54: H3 and H'5; | 3.68 | (s) — | 3.83 | (d): | H5 and Hq-| ; ~3.73 | (m) |
•««’Μ»,
I :.. ζ*·
Hg---> E; 4.38 (d): H'-|; 5.23 (dd) : H-|3.
Stage B: 9-0-(2-methoxy 2-methylethyl) oxime of 2'-O-acetyl 3-O-de(2,6-dideoxy 3-C-methyl 3-O-methyl alpha-ribo-Lhexopyranosyl) 6-O-methyl erythromycin
A mixture of 2.17 g of the product prepared in the preceding stage, 22 ml of CH2CI2 and 390 pi of acetic anhydride is agitated for one hour 30 minutes at ambient temperature. 22 ml of a saturated solution of sodium bicarbonate is added. The organic phase is washed with 10 ml of salt water. The aqueous phases are reextracted with CH2CI2. The organic phase is dried over sodium sulphate, then the solvent is evaporated off under reduced pressure.
The residue obtained is taken up in 4.25 ml of isopropyl ether then 14.9 ml of heptane. After agitation for 5 minutes, the precipitate is separated off then washed with heptane. ..After drying 1.72 g of desired product (colourless crystals) is recovered, M.p. = 200°C. Yield: 74.7%. Analytical results:
NMR (CDCI3, 300 MHz)
0.83 (t): CH3-CH2; 0.92 (d)-0.97 (d)-1.17 (d)-1.28 (d)-1.30 (d) the CH3-CH's; 1.18-1.29-1.40-1.47 the CH3-C's; 2.06 (s):
OAc; 2.26 (s): N(Me)2; 2.59 (bq): H10; 2.69 (m): H'3 and H2; 2.95 (s): OMe in position 6; 3.22 (s): OMe chain; ~3.47: H3; Hg and H'5; 3.73 (d) : H5 and 3.79 (bs): H-]-| ; 4.60 (d): Η' Ί ; 4.77 (dd): H'.2; 5.23 (dd): Hq3; 1.72 (d)-3.32- 4.63: mobile
AP/P/ 9 8/01210
ί.
ΑΡθ ο 0 887
H'S.
Stage C: 2'-O-acetyl 3-O-de(2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribo-hexopyranosyl) 6-O-methyl erythromycin
A mixture of 180 mg of the product prepared in the 5 preceding stage, 1.8 ml of ethanol/water 1/1, 23 pi of 98% formic acid and 180 mg of sodium bisulphite is agitated under reflux for 3 hours 30 minutes. The mixture is cooled down to ambient temperature and 1.8 ml of a saturated solution of sodium bicarbonate is added. After agitation for 3 minutes, extraction is carried out twice with CH2CI2· The organic phase is washed with 2 ml of a saturated aqueous solution of NaCl. The organic phase is dried over sodium sulphate and the solvent is evaporated off under reduced pressure. After purification of the residue by chromatography on silica, eluting with ethyl acetate with 2% tetrahydrofuran, 43 mg of desired product is recovered. Yield: 27%.
| Analytical | results: |
| IR: / -OH | ~3626 cm-1 (Max) |
| >=O | 3500 cm-1 1735 cm-1 |
| 1689 cm-1. |
AP/P/ 9 8/01210
Claims (12)
1) The compounds of formula (I):
in which:
either R-] represents an alkyl radical containing up to 8 carbpn atoms substituted by one or more alkyl radicals containing up to 8 carbon atoms, or by one or more aryl
20 radicals containing up to 14 carbon atoms, or R-] represents an aryl radical containing up to 14 carbon atoms, optionally substituted by one or more alkyl, alkenyl * or alkynyl radicals containing up to 8 carbon atoms, alkoxy or alkylthio radicals containing up to 8 carbon atoms, nitro,
25 CF3 radicals or by one or more halogen atoms, or Rq represents a radical:
Ra
Rb-0-C30 rc
AP/P/ 9 8/01210 in which Ra represents an alkyl or alkoxy radical containing up to 8 carbon atoms,
Rb represents an alkyl radical containing up to 8 carbon 35 atoms, optionally substituted by a heteroatom,
Rc represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms,
R2 and R3, identical or different, represent a trialkylsilyl
APO00887
a C-Rd radical,
O radical contains up to 8 carbon in which R'a, R'b, R'c and Rd represent an alkyl radical containing up to 8 carbon atoms, or an aralkyl radical containing up to 8 carbon atoms, optionally substituted by one or or more of the substituents indicated above for Rq.
2) The compounds of formula (I) as defined in claim 1 in which Rq represents a
Ra 15 I
Rb-0-CRc
20 radical in which Ra, Rb and Rc retain the same meaning as in claim 1.
3) The compounds of formula (I) as defined in claim 2, in which Ra, Rb and Rc represent a methyl radical.
4) The compounds of formula (I) as defined in one of claims \ ' 25 1 to 3, in which R2 and R3 both represent a trialkylsilyl radical.
5) , The compounds of formula (I) as defined in claim 4, in which R2 and R3 represent a trimethylsilyl radical.
6) The compound of formula (I) defined in claim 1 whose 30 name follows:
9-0-(2-methoxy-2-methylethyl) oxime of 3-O-de(2,6-dideoxy-3C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)-2'0,3-O-bis(trimethylsilyl)-6-O-methyl erythromycin.
7) Preparation process for the compounds of formula (I) as 35 defined in any one of claims 1 to 6, characterized in that the compound of formula (II):
AP/P/ 9 8/01210
APO00887
- 16 ^.0 Η is subjected to the action of an agent blocking the oxime in position 9, in order to obtain a compound of formula (III):
AP/P/ 98/01210 in which R-| retains its previous meaning, which is subjected to the action of an agent blocking the hydroxyl in position 3 and in position 2' in order to obtain the compound of formula (IV):
APOU0887
- 17 10
15 in which Ri, and R3 retain their previous meaning, which is subjected to the action of a methylation agent of the hydroxyl in position 6, in order to obtain the corresponding compound of formula (I).
8) Preparation process according to claim 7, characterized 20 in that the methylation of the compound of formula (IV) is carried out using methyl iodide in the presence of a base.
9) As new chemical products, the compounds of formulae * (III) and (IV) as defined in claim 7.
10) As chemical products defined in claim 9, the following 25 products:
9-0-(2-methoxy-2-methylethy1) oxime of 3-O-de(2,6-dideoxy-3C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) erythromycin, 9-0-(2-methoxy-2-methylethyl) oxime of 3-0-de(2,6-dideoxy-3C-me thy l-3--0-me thy 1-alpha-L-r ibo-hexopyranosy 1)-2'0, 3-030 bis (trimethylsilyl) erythromycin.
11) Use of the compounds of formula (I) as defined in any one of claims 1 to 5, characterized in that the compound of formula (I) is subjected to the following stages:
- release of the oxime in position 9,
35 - release of the hydroxyl in positions 3 and 2',
- protection of the hydroxyl in position 2' .
12) Use according to claim 11, characterized in that a compound of formula (I) is subjected to the action of formic
AP/P/ 9 8/01210
APUU0887
- 18 acid in the presence of sodium bisulphite or sodium metabisulphite, in order to directly obtain the compound formula (V):
of
AP/P/ 9 8/01210 which is subjected to the action of a protection agent of the hydroxyl in position 2' in order to obtain the compound of formula (VI):
0 z k
AP000887
- 19 in which Z represents a protective group such as the remainder of a carboxylic acid containing up to 8 carbon atoms, or a trialkylsilyl, terbutyl or triphenylmethyl radical.
5 13) Use according to claim 11, characterized in that a compound of formula (I) is subjected to the action of an agent releasing the hydroxyl in position 3 and in position 2' in order to obtain the compound of formula (VII):
;r.rj ’iie?**
AP/P/ 9 8/01210 in which R·} retains its previous meaning, which is subjected to the action of a protection agent of the OH group in position 2' in order to obtain the compound of formula (VIII) :
0 z k:
APOVO 887
- 20 L .·£·£ in which R-j retains its previous meaning and Z represents a protective group as defined previously, which is subjected to the action of an agent releasing the 9-oxo group in order to obtain the corresponding compound of formula (VI):
20 in which Z retains its previous meaning.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9510601A FR2738571B1 (en) | 1995-09-11 | 1995-09-11 | NOVEL DERIVATIVES OF 5-0-DESOSAMINYL 6-0-METHYL- ERYTHRONOLIDE A, THEIR PREPARATION PROCESS AND THEIR APPLICATION TO THE PREPARATION OF BIOLOGICALLY ACTIVE PRODUCTS |
| PCT/FR1996/001384 WO1997010251A1 (en) | 1995-09-11 | 1996-09-10 | Novel 5-o-deoaminyl 6-o-methyl erythronolide a derivatives, method for preparing same and application thereof for preparing biologically active products |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9801210A0 AP9801210A0 (en) | 1998-03-31 |
| AP887A true AP887A (en) | 2000-11-10 |
Family
ID=9482423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1998/001210A AP887A (en) | 1995-09-11 | 1996-09-10 | Novel 5-0-deoaminyl 6-0-methyl erythronolide a derivatives method for preparing same application thereof for preparing biologically active products. |
Country Status (34)
| Country | Link |
|---|---|
| US (1) | US5969161A (en) |
| EP (1) | EP0854880B1 (en) |
| JP (1) | JP4332218B2 (en) |
| KR (1) | KR100457755B1 (en) |
| CN (2) | CN1237069C (en) |
| AP (1) | AP887A (en) |
| AR (1) | AR004195A1 (en) |
| AT (1) | ATE266035T1 (en) |
| AU (1) | AU708811B2 (en) |
| BG (1) | BG63822B1 (en) |
| BR (1) | BR9610503A (en) |
| CA (1) | CA2228670C (en) |
| CZ (3) | CZ294866B6 (en) |
| DE (1) | DE69632405T2 (en) |
| DK (1) | DK0854880T3 (en) |
| EA (1) | EA000575B1 (en) |
| EE (1) | EE03774B1 (en) |
| ES (1) | ES2219698T3 (en) |
| FR (1) | FR2738571B1 (en) |
| GE (1) | GEP20022838B (en) |
| HK (2) | HK1016187A1 (en) |
| HU (1) | HU227565B1 (en) |
| IL (1) | IL123550A (en) |
| MX (1) | MX9801859A (en) |
| NO (2) | NO312678B1 (en) |
| PL (1) | PL183652B1 (en) |
| PT (1) | PT854880E (en) |
| RO (1) | RO120137B1 (en) |
| SI (1) | SI0854880T1 (en) |
| SK (3) | SK285995B6 (en) |
| TR (1) | TR199800438T1 (en) |
| UA (1) | UA53628C2 (en) |
| WO (1) | WO1997010251A1 (en) |
| ZA (1) | ZA966837B (en) |
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| US6046171A (en) * | 1997-10-29 | 2000-04-04 | Abbott Laboratories | 6,11-bridged erythromycin derivatives |
| US6124269A (en) * | 1997-10-29 | 2000-09-26 | Abbott Laboratories | 2-Halo-6-O-substituted ketolide derivatives |
| US6054435A (en) * | 1999-03-19 | 2000-04-25 | Abbott Laboratories | 6-O-substituted macrolides having antibacterial activity |
| US6420535B1 (en) | 1999-06-07 | 2002-07-16 | Abbott Laboratories | 6-O-carbamate ketolide derivatives |
| EP1483277A4 (en) * | 2002-02-15 | 2007-10-03 | Merckle Gmbh | Conjugates of biologically active compounds, methods for their preparation and use, formulation and pharmaceutical applications thereof |
| US6753318B1 (en) | 2002-07-25 | 2004-06-22 | Enanta Pharmaceuticals, Inc. | 6,11-4-carbon bridged erythromycin derivatives |
| US6841664B2 (en) | 2002-07-25 | 2005-01-11 | Enanra Pharmaceuticals, Inc. | 6,11-4-carbon bridged ketolides |
| US7273853B2 (en) * | 2002-05-13 | 2007-09-25 | Enanta Pharmaceuticals, Inc. | 6-11 bicyclic ketolide derivatives |
| US6878691B2 (en) * | 2002-05-13 | 2005-04-12 | Enanta Pharmaceuticals, Inc. | 6-11 bicyclic ketolide derivatives |
| JP2005536465A (en) * | 2002-05-13 | 2005-12-02 | エナンタ ファーマシューティカルズ インコーポレイテッド | 6,11 Bicyclic erythromycin derivatives |
| US7064110B2 (en) * | 2002-05-13 | 2006-06-20 | Enanta Pharmaceuticals, Inc. | 6-11 bicycle ketolide derivatives |
| US7910558B2 (en) * | 2002-05-13 | 2011-03-22 | Enanta Pharmaceuticals, Inc. | Bridged macrocyclic compounds and processes for the preparation thereof |
| WO2005070918A1 (en) * | 2002-05-13 | 2005-08-04 | Enanta Pharmaceuticals, Inc. | Process for the preparation of t-11 bicyclic erythromycin derivatives |
| US7135573B2 (en) * | 2002-05-13 | 2006-11-14 | Enanta Pharmaceuticals, Inc. | Processes for the preparation of O-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine |
| US6764998B1 (en) | 2003-06-18 | 2004-07-20 | Enanta Pharmaceuticals, Inc. | 6,11-4C-bicyclic 9a-azalide derivatives |
| ITMI20021726A1 (en) * | 2002-08-01 | 2004-02-02 | Zambon Spa | MACROLIDS WITH ANTI-INFLAMMATORY ACTIVITY. |
| US6645941B1 (en) | 2003-03-26 | 2003-11-11 | Enanta Pharmaceuticals, Inc. | 6,11-3C-bicyclic 9a-azalide derivatives |
| US7276487B2 (en) * | 2003-09-23 | 2007-10-02 | Enanta Pharmaceuticals, Inc. | 9a, 11-3C-bicyclic 9a-azalide derivatives |
| WO2005067564A2 (en) * | 2004-01-07 | 2005-07-28 | Enanta Pharmaceuticals, Inc. | 6-11 bicyclic erythromycin derivatives |
| WO2005070113A2 (en) * | 2004-01-09 | 2005-08-04 | Enanta Pharmaceuticals, Inc. | 9n-substituted 6-11 bicyclic erythromycin derivatives |
| JP2008522978A (en) | 2004-12-07 | 2008-07-03 | エナンタ ファーマシューティカルズ インコーポレイテッド | 3,6-bicyclolide |
| US7229972B2 (en) | 2004-12-07 | 2007-06-12 | Enanta Pharmaceuticals, Inc. | 3,6-Bicyclolides |
| WO2006065721A2 (en) | 2004-12-13 | 2006-06-22 | Enanta Pharmaceuticals, Inc. | 11, 12-lactone bicyclolides |
| US7312201B2 (en) | 2004-12-13 | 2007-12-25 | Enanta Pharmaceuticals, Inc. | Tetracyclic bicyclolides |
| US7384922B2 (en) * | 2005-05-04 | 2008-06-10 | Enanta Pharmaceuticals, Inc. | 6-11 bridged oxime erythromycin derivatives |
| EP1907392A1 (en) * | 2005-07-26 | 2008-04-09 | Merckle Gmbh | Macrolide conjugates of pyrrolizine and indolizine compounds as inhibitors of 5-lipooxygenase and cyclooxygenase |
| JP5642548B2 (en) * | 2007-09-17 | 2014-12-17 | エナンタ ファーマシューティカルズ インコーポレイテッド | 6,11-Bridged Biaryl Macrolide |
| US8354383B2 (en) * | 2007-09-17 | 2013-01-15 | Enanta Pharmaceuticals, Inc. | 6,11-bridged biaryl macrolides |
| US8273720B2 (en) * | 2007-09-17 | 2012-09-25 | Enanta Pharmaceuticals, Inc. | 6,11-bicyclolides: bridged biaryl macrolide derivatives |
| CN103232501A (en) * | 2013-04-11 | 2013-08-07 | 宜昌东阳光药业股份有限公司 | A preparation process for compounds of azithromycin or azithromycin intermediates with cladinose removed |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0272110A2 (en) * | 1986-12-17 | 1988-06-22 | Taisho Pharmaceutical Co. Ltd | Erythromycin a derivatives and method for the preparation of the same |
| EP0619320A1 (en) * | 1991-12-27 | 1994-10-12 | Taisho Pharmaceutical Co. Ltd | 5-o-desosaminylerythronolide derivative |
-
1995
- 1995-09-11 FR FR9510601A patent/FR2738571B1/en not_active Expired - Lifetime
-
1996
- 1996-08-13 ZA ZA9606837A patent/ZA966837B/en unknown
- 1996-09-05 AR ARP960104239A patent/AR004195A1/en unknown
- 1996-09-10 AT AT96931098T patent/ATE266035T1/en active
- 1996-09-10 CZ CZ20012390A patent/CZ294866B6/en not_active IP Right Cessation
- 1996-09-10 RO RO98-00685A patent/RO120137B1/en unknown
- 1996-09-10 BR BR9610503A patent/BR9610503A/en not_active IP Right Cessation
- 1996-09-10 EE EE9800065A patent/EE03774B1/en unknown
- 1996-09-10 SK SK892-2003A patent/SK285995B6/en not_active IP Right Cessation
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- 1996-09-10 KR KR10-1998-0701791A patent/KR100457755B1/en not_active IP Right Cessation
- 1996-09-10 ES ES96931098T patent/ES2219698T3/en not_active Expired - Lifetime
- 1996-09-10 SI SI9630684T patent/SI0854880T1/en unknown
- 1996-09-10 CA CA002228670A patent/CA2228670C/en not_active Expired - Lifetime
- 1996-09-10 CZ CZ1998717A patent/CZ289945B6/en not_active IP Right Cessation
- 1996-09-10 AU AU69910/96A patent/AU708811B2/en not_active Expired
- 1996-09-10 DK DK96931098T patent/DK0854880T3/en active
- 1996-09-10 IL IL12355096A patent/IL123550A/en not_active IP Right Cessation
- 1996-09-10 SK SK294-98A patent/SK283690B6/en not_active IP Right Cessation
- 1996-09-10 CN CNB001309064A patent/CN1237069C/en not_active Expired - Lifetime
- 1996-09-10 CZ CZ20012389A patent/CZ294865B6/en not_active IP Right Cessation
- 1996-09-10 AP APAP/P/1998/001210A patent/AP887A/en active
- 1996-09-10 TR TR1998/00438T patent/TR199800438T1/en unknown
- 1996-09-10 SK SK893-2003A patent/SK285853B6/en not_active IP Right Cessation
- 1996-09-10 DE DE69632405T patent/DE69632405T2/en not_active Expired - Lifetime
- 1996-09-10 GE GEAP19964228A patent/GEP20022838B/en unknown
- 1996-09-10 JP JP51169697A patent/JP4332218B2/en not_active Expired - Lifetime
- 1996-09-10 US US09/043,044 patent/US5969161A/en not_active Expired - Lifetime
- 1996-09-10 PL PL96326274A patent/PL183652B1/en unknown
- 1996-09-10 EP EP96931098A patent/EP0854880B1/en not_active Expired - Lifetime
- 1996-09-10 CN CN96198171A patent/CN1070498C/en not_active Expired - Lifetime
- 1996-09-10 HU HU9802930A patent/HU227565B1/en unknown
- 1996-09-10 EA EA199800288A patent/EA000575B1/en not_active IP Right Cessation
- 1996-09-10 WO PCT/FR1996/001384 patent/WO1997010251A1/en active IP Right Grant
- 1996-10-09 UA UA98041835A patent/UA53628C2/en unknown
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1998
- 1998-03-09 MX MX9801859A patent/MX9801859A/en unknown
- 1998-03-10 BG BG102312A patent/BG63822B1/en unknown
- 1998-03-10 NO NO19981053A patent/NO312678B1/en not_active IP Right Cessation
-
1999
- 1999-03-12 HK HK99101038A patent/HK1016187A1/en not_active IP Right Cessation
-
2002
- 2002-03-06 NO NO20021111A patent/NO315048B1/en not_active IP Right Cessation
- 2002-04-19 HK HK02103101.8A patent/HK1041489B/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0272110A2 (en) * | 1986-12-17 | 1988-06-22 | Taisho Pharmaceutical Co. Ltd | Erythromycin a derivatives and method for the preparation of the same |
| EP0619320A1 (en) * | 1991-12-27 | 1994-10-12 | Taisho Pharmaceutical Co. Ltd | 5-o-desosaminylerythronolide derivative |
| EP0619319A1 (en) * | 1991-12-27 | 1994-10-12 | Taisho Pharmaceutical Co. Ltd | 5-0-desosaminylerythronolide derivative |
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