8a- and 9a-15-membered lactams

Details 8a- and 9a-15-membered lactams 8a- and 9a-15-membered lactams

2002-01-22

2003-07-15

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C540S454000, C540S455000

Reexamination Certificate

active

06593360

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
A61K 31/70, C07H 17/08
TECHNICAL PROBLEM
The invention relates to novel 15-membered 8a- and 9a-lactams from the class of the macrolide antibiotic 6-O-methyl-erythromycin A, to intermediates for their preparation, to a process for their preparation, to their pharmaceutically acceptable addition salts with inorganic and organic acids, to their hydrates, to a process for the preparation of pharmaceutical compositions as well as to the use of pharmaceutical compositions for treatment of bacterial infections.
PRIOR ART
Erythromycin A is a macrolide antibiotic, whose structure is characterized by a 14-membered lactone ring with C-9 ketone and two sugars, L-cladinose and D-desosamine, glycosidically bound in C-3 and C-5 positions onto an aglycone moiety of the molecule (McGuire, Antibiot. Chemother. 1952; 2:281). By an oximation of C-9 ketone with hydroxylamine hydrochloride, by Beckmann rearrangement of the obtained 9(E)-oxime and by a reduction of the formed 6,9-imino ether there is obtained 9-deoxo-9a-aza-9a-homoerythromycin A, the first semisynthetic macrolide with a 15-membered azalactone ring (Kobrehel G. et al., U.S. Pat. No. 4,328,334, 5/1982). By means of a reductive methylation of 9a-amino group, azithromycin, a prototype of a novel class of 9a-azalide antibiotics was synthesized (Kobrehel G. et al., BE 892 357, 7/1982). In addition to having a broad antimicrobial spectrum including also Gram-negative bacteria, azithromycin is also characterized by a long biological half-life, a specific transport mechanism to the site of use and a short therapy time. Azithromycin easily penetrates and accumulates inside human fagocyte cells resulting in improved activity on intracellular pathogenic microorganisms, from classes Legionella, Chlamydia and Helicobacter.
It is known as well that by a O-methylation of C-6 hydroxyl group clarithromycin (6-O-methyl-erhytromycin A) is obtained (Morimoto S. et al., J. Antibiotics 1984. 37. 187). In relation to erythromycin A, clarithromycin is much more stable in acidic medium and exhibits improved in vitro activity against Gram-positive bacterial strains (Kirst H. A. et al., Antimicrobial Agents and Chemother., 1989, 1419).
By recent research on 14-membered macrolides, a novel type of macrolide antibiotics. ketolides, has been discovered, whose structure is characterized by a 3-keto croup instead of a neutral sugar, L-cladinose (Agouridas C. et al., EP 596802 A1 5/1994; Le Martret O., FR 2697524 A1 5/94). Ketolides exhibit significantly improved in vitro activity against MLS (macrolide, lincosamide and streptogramin B) induced-resistant organisms (Jamjian C., Antimicrob. Agents Chemother., 1997, 41, 485).
It has been described as well that by Beckmann rearrangement of 6-O-methyl-erythromycin A 9(E)- and 9(Z)-oximes, hydrolysis of cladinose of the obtained 8a- and 9a-lactams, protection of 2′-hydroxyl group of desosamine, an acylation reaction, an oxidation of 3-hydroxyl group and by deprotection, there are obtained 15-membered 8a- and 9a-ketolides from the class of 6-O-methyl-erythromycin A (Lazarevski G. et al., PCT/HR 99/00004, 4/99).
According to known and established prior art, novel 15-membered 8a- and 9a-lactams from the class of 6-O-methyl-erythromycin A, which are the object of the present invention, their pharmaceutically acceptable addition salts with organic or inorganic acids, their hydrates, methods and intermediates for their preparation and methods for their preparation and use as pharmaceutical preparations have hitherto not been described. The object of this invention is preparation of 11,12-substituted derivatives of 6-O-methyl-erythromycin A 8a- and 9a-lactams and their 3-hydroxy and 3-keto derivatives. A further object of the present invention are 3-acyl derivatives of 6-O-methyl-erythromycin A 8a- and 9a-lactams and 3-acyl-derivatives of 11,12-substituted 6-O-methyl-erythromycin A 8a- and 9a-lactams. Novel 15-membered 8a- and 9a-lactams of the present invention are potential antibiotics for the treatment of Gram-positive and Gram-negative susceptible resistant strains.
DESCRIPTION OF TECHNICAL PROBLEMS WITH EXAMPLES
Novel 15-membered 8a- and 9a-lactams from the class of 6-O-methyl-erythromycin A of the general formula (I)
their pharmaceutically acceptable addition salts with inorganic or organic acids and their hydrates, wherein
A stands for NH group and B simultaneously stands for C═O group, or
A stands for C═O group and B simultaneously stands for NH group,
R
1
stands for OH group, L-cladinosyl group of formula (II)
or R
1
stands for a group of formula (III),
 wherein
Y stands for hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkyl group with at least one incorporated O, N or S atom or Y stands for (CH
2
)
n
—Ar, wherein (CH
2
)
n
stands for alkyl and n stands for 1-10, with or without incorporated O, N or S atoms, and Ar stands for 5-10-membered monocyclic or bicyclic aromatic ring containing 0-3 O, N or S atoms, which is unsubstituted or substituted with 1-3 groups representing halogen, OH, OMe, NO
2
, NH
2
, amino-C
1
-C
3
alkyl, amino-C
1
-C
3
dialkyl, CN, SO
2
NH
2
, C
1
-C
3
alkyl, or
R
1
together with R
2
stands for ketone,
R
2
stands for hydrogen or together with R
1
stands for ketone,
R
3
stands for hydrogen or C
1
-C
4
alkanoyl group,
R
4
stands for hydrogen or together with R
5
stands for ketone,
R
5
stands for OH, NH
2
, amino-C
1
-C
3
alkyl or amino-C
1
-C
3
dialkyl, O(CH
2
)
n
Ar or S(CH
2
)
n
Ar, wherein (CH
2
)
n
and Ar have the above meanings, or together with R
4
stands for ketone,
R
6
stands for hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkyl group with at least one incorporated O, N or S atom, or (CH
2
)
n
—Ar group, wherein (CH
2
)
n
and Ar have the above meanings, or
R
5
and R
6
together with intervening atoms form an additional ring of formula (IV)
 wherein
Z stands for CH
2
, C═O, C(NH), SO, SO
2
, CH
2
CO, COCH
2
, CH
2
CH
2
CO. COCH
2
CH
2
or CH
2
CH
2
, and
X stands for hydrogen, C
1
-C
3
alkyl, NH
2
, amino-C
1
-C
3
alkyl or amino-C
1
-C
3
dialkyl or (CH
2
)
n
—Ar group, wherein (CH
2
)
n
and Ar have the above meanings,
are obtained as follows:
Step 1:
The first step of the invention includes a reaction of 6-O-methyl-9a-aza-9a-homo-erythromycin A or 6-O-methyl-8a-aza-8a-homoerythromycin A, obtained according to PCT/HR 99/00004, 4/99, with ethylene carbonate in the presence of inorganic or organic bases, preferably potassium carbonate, in a reaction-inert solvent, preferably in ethyl acetate, yielding corresponding 11,12-cyclic carbonates of the general formula (I), wherein A stands for NH and B simultaneously stands for C═O group, or A stands for C═O group and B simultaneously stands for NH group, R
1
stands for L-cladinosyl group of formula (II) and R
2
, R
3
and R
4
are mutually the same and stand for hydrogen, R
5
and R
6
together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C═O group.
Step 2:
11,12-cyclic carbonates obtained in the Step 1, are subjected to hydrolysis with strong acids, preferably with 0.25-1.5 N hydrochloric acid, in a mixture of water and lower alcohols, preferably methanol, ethanol or isopropanol, over 10-30 hours at room temperature, yielding 3-decladinosyl derivatives of general formula (I), wherein A stands for NH group and B simultaneously stands for C═O group, or A stands for C═O group and B simultaneously stands for NH group, R
1
stands for OH group, R
2
, R
3
and R
4
are mutually the same and stand for hydrogen, and R
5
and R
6
together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C═O group.
Step 3:
3-Decladinosyl derivatives from the Step 2 are subjected to a selective acylation of the hydroxyl group in 2′-position. Acylation is carried out with chlorides or anhydrides of carboxylic acids with up to 4 carbon atoms, preferably with acetic acid anhydride, in the presence of inorganic or organic bases, in a reaction-inert solvent at a temperature from 0-30° C., yi

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