Derivatives from the class of oleandomycin

Details Derivatives from the class of oleandomycin Derivatives from the class of oleandomycin

2001-07-02

2003-06-03

Barts, Samuel (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S007100, C536S004100, C536S124000, C514S028000, C514S029000, C514S025000, C514S034000

Reexamination Certificate

active

06573367

ABSTRACT:

TECHNICAL FIELD
1. Technical Problem
The invention relates to novel compounds from the class of the macrolide antibiotic oleandomycin, tointermediates for the preparation thereof, to a process for preparing them as well as to pharmaceutically acceptable addition salts thereof with inorganic or organic acids.
2. Prior Art
Oleandomycin is a macrolide antibiotic (U.S. Pat. No. 2,757,123) having an activity spectrum similar to that of erythromycin A. The oleandomycin structure is characterized by a 14-member lactone ring with a keto group in C-9 position, by the sugar desosamin in C-5 position and by the sugar oleandrose in C-3 position as well as by three OH groups. It differs from other polyoxo macrolides by an exocyclic epoxide ring on C-8 atom. Earlier investigations (JACS 82, 3225-3227, 1960; JOC 51, 5397-5400, 1986) showed its exceptional sensitivity both in acidic and basic conditions. In an acidic medium C-8 epoxide is opened, oleandrose is cleaved and a contraction of the aglycone ring takes place. The action of a base causes a dehydratation of H-10 and OH-11 under the generation of C-10/C-11 double bond to give anhydrooleandomycin. All these transformations cause a loss of the antibiotic action.
It is known that similar transformations at erymromycin A with OH groups participating are successfully inhibited by O-methylation thereof (Watanabe Y. and al, U.S. Pat. No. 4,331,803, 5/1982). By the reaction of erymromycin A with benzyloxycarbonyl chloride and then by methylation of the obtained 2′-O,3′-N-bis(benzyloxycarbonyl)-derivatives, after elimination of protecting groups and N-methylation, there are obtained, in addition to 6-O-methyl erythromycin (CLARITHROMYCIN), significant amounts of 11-O-methyl erythromycin and polysubstituted analogues (Morimo S. et al, J. Antibiotics 1984, 37, 187). Clarithromycin is significantly more stable in an acidic medium than erythromycin A and shows enhanced in vitro activity against Gram positive bacterial strains (Kirst H. A. et al. Antimicrobial Agents and Chemother., 1989, 1419). Similarly, also a series of O-methyl derivatives of azythromycin was synthesised (Kobrehel G. et al, U.S. Pat. No. 5,250,518, 5/1993).
Our efforts to inhibit the formation of an inactive anhydrooleandomycin by O-methylation of C-11 hydroxyl group, retroaldol fragmentation, dehydratation and isomerisation took place and led to a series of linear and cyclic derivatives of oleandomycin, not yet disclosed so far, which may serve as intermediates for chimeric oleandomycins with potential biological action.
The synthesis of these derivatives involves a reaction of oleandomycin with benzyloxycarbonyl chloride to obtain 2′-O,3′-N-bis(benzyloxycarbonyl)-3′-N-demethyl oleandomycin, a reaction with methyl iodide in the presence of sodium hydride, an elimination of protecting groups on 2′ and 3′ positions and reductive 3′-N-methylation.
Oleandomycin derivatives according to the present invention and their pharmaceutically acceptable addition salts with inorganic or organic acids, methods and intermediates for the preparation thereof have not been disclosed in Prior Art.
DESCRIPTION OF THE INVENTION WITH EXAMPLES
Novel derivatives of oleandomycin of the general formula (I)
wherein
R
1
has the individual meaning of —CH
2
CH
3
group, of a fragment of the formula (II), together with R
2
has the meaning of a fragment of the formula (III) or together with R
4
has the meaning of a fragment of the formula (IV) or a fragment of the formula (V)
R
2
together with R
3
has the meaning of a ketone or together with R
1
has the meaning of a fragment of the formula (III),
R
3
has the individual meaning of OH group or together with R
2
has the meaning of a ketone,
R
4
has the individual meaning of a methyl group, or together with R
1
has the meaning of a fragment of the formula (IV) or of a fragment of the formula (V),
R
5
has the individual meaning of hydrogen or a benzyloxycarbonyl group,
R
6
has the individual meaning of hydrogen, a methyl group or a benzyloxycarbonyl group,
and their pharmaceutically acceptable addition salts with inorganic or organic acids, are obtained as follows.
Fragment IV is one of one of sixteen diasteroisomers of fragment V. As is known to persons of skill in the chemical arts, a wedge-shaped bond represents bonding to a group projecting above the plane of the paper. As is known to persons of skill in the chemical arts, a stippled bond represents bonding to a group projecting below the plane of the paper. For purposes of lexicography, we individually name the sixteen diastereoisomers of Fragment V with respect to the projection of the various bonds starting with the bond closest to the top of the page, With reference to fragment IV, the bond to methyl nearest the top of the page, projects up (U), the bond to hydroxyl projects up (U), continuing down the page, the bond to methyl projects down (D), and the bond to methyl towards the bottom of the page projects down (D). Thus we name Fragment IV, the UUDD diastereoisomer of Fragment V, Fragment V
1
. Retaining the same naming convention, there are four UU diastereoisomers (UUDD, V1; UUUD, V2; UUDU, V3; UUUU, V4). There are four DD diastereoisomers (DDDD, V5; DDUD, V6; DDDU, V7; DDUU, V8). There are four DU diastereoisomers (DUDD, V9; DUUD, V10; DUDU, V11; DUUU, V12). There are four UD diastereoisomers (UDDD, V13; UDUD, V14; UDDU, V15; UDUU, V16)
By subjecting oleandomycin of the formula (VI) to a reaction with benzyloxycarbonyl chloride in the presence of bases, preferably sodium hydrogen carbonate, in a solvent inert in the reaction, preferably benzene or toluene, there is obtained 2′-O,3′-N-bis(benzyloxycarbonyl)-3′-N-demethyl-oleandomycin of the general formula (I), wherein R
1
together with R
4
has the meaning of a fragment of the formula (IV), R
2
together with R
3
has the meaning of a ketone and R
5
and R
6
are the same and have the meaning of a benzyloxycarbonyl group.
Step 2:
By a reaction of 2′-O,3′-N-bis(benzyloxycarbonyl)-3′-N-demethyl-oleandomycin from Step 1 with 1.3-3.25 equivalents of the corresponding methylation agent, preferably methyl iodide, and 1.1-3.75 equivalents of the corresponding base, preferably sodium hydride, at a temperature from −15° C. to room temperature, preferably at 0-5° C., in an appropriate aprotic solvent or solvent mixture, preferably DMSO-THF=1:1, and by separation on a silica gel column in the system toluene-ethyl acetate=1:1 there is obtained
a compound 2A of the general formula (I), wherein R
1
has the individual meaning of —CH
2
CH
3
group, R
2
together with R
3
has the meaning of a ketone, R
4
is a methyl group and R
5
and R
6
are the same and have the meaning of a benzyloxycarbonyl group,
a compound 2B of the general formula (I), wherein R
1
together with R
4
has the meaning of a fragment of the formula (V), R
2
together with R
3
has the meaning of a ketone and R
5
and R
6
are the same and have the meaning of a benzyloxycarbonyl group, and
a compound 2C of the general formula (I), wherein R
1
has the individual meaning of a fragment of the formula (II), R
2
together with R
3
has the meaning of a ketone, R
4
is a methyl group and R
5
and R
6
are the same and have the meaning of a benzyloxycarbonyl group.
The relative ratio of chromatographically homogenous products depends upon the equimolar ratio of reactants.
Step 3:
Each of the oleandomycin derivatives from Step 2 is separately subjected to a hydrogenolysis reaction in order to eliminate protecting benzyloxycarbonyl groups in 2′ and 3′ positions according to the method by E. H. Flynn et al (Journal of American Chemical Society, 77, 3104, 1950). Hydrogenolysis is carried out in a lower alcohol solution, preferably in ethanol, in the presence of NaOAc/HOAc buffer (pH 5), with a catalyst such as palladium black or palladium on carbon, under hydrogen pressure of 10
5
Pa at room temperature to obtain, respectively,
in case of 2A, a compound 3A of the general for

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