HRP980316A2 - 9-oxime erythromycin derivatives - Google Patents

Description

State of the art

This invention relates to new 3-keto-9-oxime-11,12-carbazate or carbamate derivatives of 6-O-methyl-erythromycin A. The compounds of this invention are applicable as antibiotic agents in mammals, including humans, as well as in fish and a bird. The compounds of the described invention are broad-spectrum macrolide antibiotics that are effective against infections caused by certain gram-positive and gram-negative bacteria, as well as protozoa.

Brief description of the invention

The described invention relates to compounds of formula I:

[image]

and to their pharmaceutically acceptable salts, where

X is -CR7R8 or -NR7-; or

X taken together with R 2 forms -N=CR 4 R 5 ; or

X and R2 taken together form a heterocyclic ring of formula XVI:

[image]

wherein in said ring of formula XVI, r and p are each independently an integer from 1 to 3, q is 0 or 1, and X 1 is -CH 2 -, O, S, -C(O)-, -C(S)-, - SO2-, -CH=CH-, -CH(OH)CH(OH)- or -NH-; and where the (CH2)r and (CH2)p portions of said ring of formula XVI are optionally substituted with 1 to 4 substituents, and the nitrogen atom where X1 is -NH- is optionally substituted with one substituent, said optional substituents being independently selected from the group consisting of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo, nitro, cyano, 5- to 10-membered heterocycle, C1-C10 alkyl, -NR7R8, C6-C10 aryl, -S(O)n(C1-C10 alkyl) where n is an integer from 0 to 2, and -SO2NR7R8;

R1 is H or C1-C10 alkyl, wherein 1 to 3 carbon atoms of said alkyl are optionally replaced with a heteroatom selected from O, S and N, and said alkyl is substituted with 1 to 3 substituents independently selected from the group consist of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo, nitro, cyano, 5- to 10-membered heterocycle, C1-C10 alkyl, -NR7R8, C6-C10 aryl , -S(O)n(C1-C10 alkyl) where n is an integer from 0 to 2, and -SO2NR7R8;

R2 is

(i) H, R4, -C(O)R4, -C(O)OR4, or -(CR7R8)mR3 when X is -NR7, or

(ii) H, R4 or -(CR7R8)mR3 when X is -CR7R8-,

where in both cases, ie for (i) and (ii) m is an integer from 0 to 6, and both R7 and R8 can vary for each iteration where m is greater than 1;

each R3 is independently a C6-C10 aryl or a 5- to 10-membered heterocycle, wherein said aryl and heterocycle groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo nitro, cyano, 5- to 10- membered heterocycle, C6-C10 aryl, C1-C10 alkyl, -NR7R8, -S(O)n(C1-C10 alkyl ) where n is an integer from 0 to 2, and -SO2NR7R8; and

each R4 and R5 is independently selected from H and C1-C12 alkyl wherein 1 or 2 carbon atoms of said alkyl are optionally substituted with a heteroatom selected from O, S and N, and wherein said alkyl is optionally substituted with 1 to 3 of substituents independently selected from the group consisting of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo, nitro, cyano, C1-C10 alkyl, -NR7R8, C6-C10 aryl , 5- to 10-membered heterocycle, -S(O)n(C1-C10 alkyl) where n is an integer from 0 to 2, and -SO2NR7R8;

R6 is H, -C(O)R3 or C1-C18 alkanoyl, where in the alkyl part of said alkanoyl group 1 or 2 carbon atoms can optionally be replaced by a heteroatom selected from O, S and N; and

each R 7 and R 8 is independently H or C 1 -C 6 alkyl.

Even more specific embodiments of the present invention include compounds of formula I wherein R 6 is H.

Other more specific embodiments of the present invention include compounds of formula I wherein X is -NH-.

Other more specific embodiments of the present invention include compounds of formula I wherein R 1 is H, benzyl, C 1 -C 3 alkyl, or -CH 2 O(CH 2 ) 2 OCH 3 .

Other more specific embodiments of the present invention include compounds of formula I wherein R 2 is -(CH 2 )m R 3 , where m is an integer from 0 to 6, and R 3 is a 5- to 10-membered heterocycle, or C 6 -C 10 aryl. Specific embodiments of R3 include quinolin-4-yl, 4-phenyl-imidazol-1-yl, imidazo(4,5)pyridin-3-yl, 4-pyridin-3-ylimidazol-1-yl, and pyridin-3-yl.

Examples of preferred compounds of this invention include:

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-pyridin-3-yl-imidazol-1-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3 -oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-pyridin-3-yl-imidazol-1-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3 -oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(imidazo(4,5-b)pyridin-3-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3 -oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(imidazo(4,5-b)pyridin-3-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3 -oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(7-methoxy-quinolin-4-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11 ,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(7-methoxy-quinolin-4-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11 ,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-benzoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

19-deoxo-1-deoxy-5-O-desosaminyl-11-(3-benzoimidazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

19-deoxo-1-deoxy-5-O-desosaminyl-11-(3-benzoimidazol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indazol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-carbazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-carbazol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(5-phenyl-1H-pyrrol-2-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(5-phenyl-1H-pyrrol-2-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-imidazol-1-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-imidazol-1-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-(4-chlorophenyl)-(1,2,4)oxa-diazol-5-yl)-propyl)hydrazo-9- hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-(4-chlorophenyl)-(1,2,4)oxa-diazol-5-yl)-propyl)hydrazo-9- methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

19-deoxo-1-deoxy-5-O-desosaminyl-11-(3-(3-(4-methoxyphenyl)-(1,2,4)oxa-diazol-5-yl)-propyl)hydrazo-9- hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

19-deoxo-1-deoxy-5-O-desosaminyl-11-(3-(3-(4-methoxyphenyl)-(1,2,4)oxa-diazol-5-yl)-propyl)hydrazo-9- methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-(4-pyridin-4-yl)-(1,2,4)oxa-diazol-5-yl)-propyl) hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-(4-pyridin-4-yl)-(1,2,4)oxa-diazol-5-yl)-propyl) hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-naphthalen-1-yl-propyl)-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-naphthalen-1-yl-propyl)-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-1-yl-propyl)-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-1-yl-propyl)-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-2-yl-propyl)-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-2-yl-propyl)-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(1H-indol-3-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11, 12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(1H-indol-3-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11, 12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-4-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-4-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-3-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-3-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-2-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-2-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-phenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-phenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-bis-(3-phenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-bis-(3-phenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-methoxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-methoxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-methoxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-methoxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(2-methoxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(2-methoxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-hydroxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-hydroxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-methoxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-methoxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-phenylethyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-phenylethyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(4-phenylbutyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(4-phenylbutyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-furan-2-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-furan-2-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-thiophen-2-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-thiophen-2-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrrol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrrol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrazol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-pyridin-3-yl-thiazol-4-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A , 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-pyridin-3-yl-thiazol-4-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A , 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-phenyl-thiazol-5-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12 - carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-phenyl-thiazol-5-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12 - carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-1H-imidazol-2-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-1H-imidazol-2-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-10-epi-11-hydrazo-9-benzoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-10-epi-11-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

and pharmaceutically acceptable salts of the aforementioned compounds.

The invention also relates to a pharmaceutical preparation for the treatment of bacterial infection or protozoan infection in mammals, fish or birds, which includes a therapeutically effective amount of the compound of formula I, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

The invention also relates to a method for treating a bacterial infection or a protozoan infection in mammals, fish or birds, which includes the application to said mammal, bird or fish of a therapeutically effective amount of the compound of formula I, or its pharmaceutically acceptable salt.

The term "treatment", as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial infection or a protozoan infection as provided in the process of the described invention.

The term "bacterial infection" or "protozoan infection" as used herein, unless otherwise noted, includes bacterial infections and protozoan infections occurring in mammals, fish and birds, as well as disorders associated with bacterial infections and protozoan infections , which can be treated or prevented using antibiotics, such as the compounds of the described invention. Such bacterial or protozoan infections and disorders associated with such infections include the following: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis associated with infection with Streptococcus pneumoniae, Haempphilius influenzae, Moraxella catarrhalis, Staphylococcus aureus or Peptostreptococcus spp. ; pharyngitis, rheumatic fever and glomerulonephritis associated with infection with Streptococcus pyogenes, Group C and G streptococci, Clostridum diphteriae or Actinobacillus haemolyticum; respiratory tract infections related to infection with Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae or Chlamydia pneumoniae; uncomplicated tissue and soft tissue infections, abscesses and osteomyelitis and puerperal fever associated with infection with Staphylococcus aureus, coagulase-positive staphylococci (ie S. Epidermidis, S. hemolyticus., etc.), Streptococcus pyogenes, Streptococcus, Streptococcal groups C-F (minute- colony streptococci) virdans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated urinary tract infections related to infection with Staphylococcus saprophyticus or Enterococcus spp.; urethritis and cervicitis and a sexually transmitted compound associated with infection with Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum or Neiserria gonorrheae; toxic diseases related to infection with S. aureus (food poisoning and toxic shock syndromes) or Groups A, B and C streptococci; ulcers associated with Helicobacter pylori infection; systemic febrile syndromes related to Borrelia recurrentis infection; Lyme disease associated with infection with Borrelia burgdorferi; conjunctivitis, keratitis dacrocystitis associated with infection with Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. Pneumoniae, S. pyogenes, H. influenzae or Listeria spp.; extended Mycobacterium avium complex disease (MAC disease) associated with infection with Mycobacterium avium or Mycobacterium intracellulare; gastroenteritis associated with infection with Campylobacter jejuni; intestinal protozoa associated with infection with Cryptosporidium spp.; odontogenic infection related to viridans streptococci; chronic cough associated with infection with Bordetella pertussis; gas gangrene associated with infection with Clostridum perfringens or Bacteroids spp.; and atherosclerosis related to infection with Helicobacter pylori or Chlamydia pneumoniae.

Bacterial and protozoan infections in animals, and disorders associated with such infections, which may be treated or prevented include the following: bovine respiratory disease associated with infection with P. haem., P. multocida, Mycoplasma bovis or Bordetella spp.; enteric disease of the cow caused by infection with E. coli or protozoa (for example coccidia, crptosporidia, etc.); mastitis of dairy cows caused by Staph. aureus, Strep. Uberis, Strep. agalactiae, Strep. dysgalctiae, Klebsiell spp., Corynbacterium or Entercoccus spp.; respiratory disease in pigs caused by infection with A. pleuro., P. multocida or Mycoplasma spp.; enteric disease in pigs related to infection with E.coli, Lawsonia intracellularis or Serpulina Hyodyisinteriae; leg disease in a cow related to infection with Fusobacterium spp.; cow metritis associated with E. coli infection; hairy warts in a cow associated with infection with Fusobacterium necrophorum or Bacteroides nodosus; pink eyes in a cow associated with Moraxella bovis infection; premature calving in cows associated with infection with protozoa (for example neosporium); urinary tract infection in dogs and cats related to infection with Staph. epidermidius intermedius, coagulase neg. staph. or P. multocida; and dental or oral infections in dogs and cats associated with infection with Alaligenes spp., Bacteroides spp., Clostridium spp., Enterbacter spp., Eubacterium, Peptostreptococcus, Porphyrpmonas, or Prevotella. Other bacterial and protozoan infections and disorders associated with such infections that may be treated or prevented by the method of the present invention are listed in J.P. Sanford et al.: "The Stanford Guide To Antimicrobial Therapy", 26th ed., Antimicrobial Therapy Inc., ( 1996).

The invention also relates to a process for obtaining a compound of the formula I and its pharmaceutically acceptable salts, where R1, R2, R6 and X are as defined above, which comprises treating a compound of the formula:

[image]

wherein X and R2 are as defined above, with a compound of formula R1ONH2•HCl or R1ONH2, where R1 is as defined for said compound of formula I, and in the presence of an acid in a polar solvent such as methanol, ethanol or isopropyl alcohol. Preferably, said amount is Py•HCl, where Py stands for pyridine or Et3N•HCl.

In the chemical structures shown here, the wavy line indicates that the stereochemistry at the chiral center to which this line is attached can be of the R or S configuration when the wavy line is attached to the carbon atom. In a compound of formula I, the wavy line at the 10-position of the macrolide ring indicates that the methyl group can be of either the R or S configuration at that position. In a compound of formula I, the wavy line attached to the oxime nitrogen at position 9 of the macrolide ring indicates that the -OR1 group is in the Z configuration.

The term "halo", as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having normal, cyclic or branched groups or mixtures thereof. Said alkyl group may include one or two double or triple bonds. It is understandable that cyclic groups require at least 3 carbon atoms in the mentioned alkyl group.

The term "alkanoyl", as used herein, unless otherwise indicated, includes -C(O)-alkyl groups where "alkyl" is as defined above.

The term "aryl" as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic carbon by removal of one hydrogen, such as phenyl or naphthyl.

The term "5- to 10-membered heterocycle" as used herein, unless otherwise noted, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms, each selected from O, S, and N wherein each heterocyclic group has from 5 to 10 atoms in its ring system. Heterocyclic groups include fused benzene ring systems and ring systems substituted with one or more oxo groups. An example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl and thiazolyl. Heterocyclic groups having a fused benzene ring include benzimidazolyl.

The term "pharmaceutically acceptable salts" as used herein, unless otherwise indicated, includes salts of acid or base groups which may be present in compounds of formula I. Compounds of formula I which are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to obtain a pharmaceutically acceptable acid addition salt of such base compounds of formula I are those that form non-toxic acid addition salts, for example salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [for example, 1,1'-methylene-bis(2-hydroxy-3-naphthoate)] salts.

Those compounds of formula i which are acidic in nature are capable of forming base salts with various pharmacologically acceptable salts. Examples of such salts include alkali metal salts or alkaline earth metal salts, especially sodium and potassium salts.

The described invention also includes all radiolabelled forms of the compounds of formula I, and their pharmaceutically acceptable salts, where the radiolabel is chosen from 3H, 11C and 14C. Such radiolabeled compounds are applicable as research or diagnostic agents.

Certain compounds of formula I may have asymmetric centers, and therefore may exist in different enantiomeric forms. This invention relates to the use of all optical isomers and stereoisomers of compounds of formula I and their mixtures. More specifically, the invention includes the R and S configurations of the methyl group at the C-10 position of the macrolide ring of formula I, and the E and Z configurations of the -OR1 group attached to the nitrogen of the oxime group at the C-9 position of the macrolide ring of formula I. The compounds of formula I can also exist also as tautomers. This invention relates to the use of all such tautomers and their mixtures.

Detailed description of the invention

Preparation of the compounds of the described invention is illustrated in the following schemes.

[image]

[image]

[image]

[image]

[image]

In the above scheme "Ac" denotes an acetyl group. The compounds of the described invention are easily obtained.

Scheme 1 illustrates the general synthesis of the compounds of the described invention. In scheme 1, the starting compound of formula II can be obtained as described in patent no. 5,543,400 (issued Aug. 6, 1996). In general, the intermediate compound of formula III can be prepared as described in U.S. Pat. patent no. 5,543,400, supra, U.S. Pat. patent no. 5,527,780 (published June 18, 1996), United Kingdom patent application no. 2288174 (filed Oct. 11, 1995), and G. Griesgraber et al.: "3-keto-11,12-carbazate derivatives of 6-O-methylerythromycin A, Journal of Antibiotics" 49 (5), p. 465-477, (1996).

In step 1 of Scheme 1, compounds of formula III, wherein X is -CR7R8- and R2 is as defined above, can be obtained by treating a compound of formula II with a compound of formula H2N-X-R2, wherein X and R2 are as indicated for said compound of formula III, in a solvent such as acetonitrile, dimethylformamide (DMF), tetrahydrofuran (THF), dimethoxyethane or dimethylsulfoxide (DMSO), at a temperature in the region of about 50°C to 90°C, for a period of around 4 to 10 o'clock. Obtaining compounds of formula III where X is -CR7R8 is described in more detail in the aforementioned patents no. 5,543,400 and 5,527,780. Compounds of formula III, where X is -NH- and R 2 is as defined above can be obtained by treating a compound of formula II with a compound of formula H 2 NNHR 2 , where R 2 is as defined above, in a solvent such as acetonitrile, dioxane or DMSO, at a temperature in the region of about 40 °C to 90 °C, over a period of about 12 hours. The preparation of the compound of formula III wherein X is -NH- is described in more detail in the above-mentioned United Kingdom Patent Application No. 2,288,174.

In step 2 of Scheme 1, compounds of formula I can be obtained by treating a compound of formula III with a compound of formula R1ONH2•HCl or R1ONH2, where R1 is as defined above, in the presence of an acid such as Py•HCl, where Py is pyridine or Et3N•HCl, in a polar solvent, preferably methanol or ethanol or isopropyl alcohol, at a temperature in the region of about 65 °C to 95 °C, for a period of about 10 hours to 6 days.

Scheme 2 illustrates an alternative procedure for preparing compounds of formula I where X is -NH-. In Scheme 2, the compound of formula IV can be obtained according to the procedures described in Baker et al.: "Journal of Organic Chemistry", 53, p. 2340, (1988).

In step 1 of Scheme 2, a compound of formula V can be obtained by treating a compound of formula IV with hydrazine, according to the procedure described above for obtaining a compound of formula III where X is -NH-. The preferred compound of formula V is obtained by treating the compound of formula IV with anhydrous hydrazine, in a solvent such as MeCN or DMF, at a temperature of about 60°C to 90°C, for about 12 hours.

In step 2 of Scheme 2, a compound of formula VI can be prepared by treating a compound of formula V with an acid such as hydrochloric acid, in a solvent such as methanol or ethanol.

In step 3 of Scheme 2, a compound of formula VII can be obtained by treating a compound of formula VI with a compound of formula R3-(CH2)m-1-C(O)H, where m is 1 to 7 and R3 is as defined above, in an anhydrous solvent such as isopropanol, at a temperature in the region of about 80 °C to 90 °C.

In steps 4 and 5 of Scheme 2, the hydroxy group at the C-2' position of the compound of formula VII is protected in the acetate form by treating the compound with acetic anhydride to form the compound of formula VIII, which is further followed by oxidation of the hydroxy group at position 3 to obtaining a carbonyl group. This is preferably done by treating the compound of formula VII with acetanihydride, in a solvent such as CH2Cl2, at room temperature to give the compound of formula VIII. A compound of formula IX can be obtained by treating a compound of formula VIII, in a solvent such as CH2Cl2, with DMSO, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC) and pyridinium trifluoroacetate (Py•TFA) at room temperature . A compound of formula X can be obtained by treating a compound of formula IX with a reducing agent such as NaBH 3 CN in a solvent such as methanol at room temperature. The compound of formula XI can be prepared as described above for step 2 of scheme 1.

Scheme 3 illustrates an additional procedure for preparing compounds of formula I where X is -NH. In scheme 3, the compound of formula XII can be obtained according to the procedures described in Griesgraber et al.: "Journal of Antibiotics" 49 (5), p. 465-477, (1966).

In step 1 of Scheme 3, a compound of formula XII can be obtained by treating a compound of formula XII with a compound of formula R1ONH2•HCl or R1ONH2, in the presence of an acid such as Py•HCl, where Py is pyridine or Et3N•HCl, in such a polar solvent such as ethanol, methanol or isopropyl alcohol, at a temperature in the range of about 65°C to 95°C, for a period of about 10 hours to 4 days.

In step 2 of scheme 3, a compound of formula XIII can be converted to a compound of formula XIV according to the procedure of step 3 of scheme 2.

In step 3 of scheme 3, a compound of formula XIV can be converted to a compound of formula XV according to the procedure of step 6 of scheme 2.

The compounds of the described invention may have asymmetric carbon atoms. Such diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical and chemical differences, by methods known to those skilled in the art, for example by chromatography or fractional crystallization. Enantiomers can be separated by converting enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (for example an alcohol), separating the diastereomers and converting (for example hydrolysis) the individual diastereomers into the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers, are considered part of the present invention.

Compounds of formula I which are basic in nature can form a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for use in animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt, and then simply convert this back into the free base by treatment with an alkaline reagent, and then sequentially converts this free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of this invention are readily obtained by treating the base compound with a substantially equivalent amount of a selected mineral or organic acid, in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding a solution of a suitable mineral or organic acid.

Those compounds of formula I which are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts and alkaline earth metal salts, especially potassium and sodium salts. These salts can be obtained using conventional techniques. Chemical bases used as reagents for the preparation of pharmaceutically acceptable base salts are those which form non-toxic base salts with acid compounds of formula I. Such non-toxic base salts include those derived from pharmacologically acceptable cations, such as sodium, potassium, calcium and magnesium, etc. These salts can be obtained by treating the corresponding acid compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, these salts can also be obtained by mixing alkanoyl solutions of acid compounds and the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as before. In both cases, in order to ensure completion of the reaction and maximum yields of the desired final product, stoichiometric amounts of reagents are preferably used.

The activity of the compounds of the described invention against bacterial and protozoan pathogens was demonstrated by the ability of the compounds to inhibit the growth of defined types of human pathogens (experiment I) or animal pathogens (experiments II and III).

Experiment I

Trial I, described below, uses common methodology and interpretation of criteria, and is provided to provide direction for chemical modifications that may lead to compounds that overcome defined mechanisms of macrolide resistance. In Experiment I, the panel of bacterial species was designed to include a variety of target pathogenic species, so as to include representative examples of macrolide resistance mechanisms that are characteristic. The use of this panel enables determination of the chemical structure/activity relationship with respect to ability, spectrum of activity, and structural elements or modifications that may be required to overcome resistance mechanisms. Bacterial pathogens covered by the test panel are shown below in the table. In many cases, both a macrolide-susceptible parental strain and a derived macrolide-resistant strain were available to ensure a more accurate examination of the compounds' ability to overcome the resistance mechanism. Species containing the ermA/ermB/ermC gene are resistant to macrolide, lincosamide and streptogramin B antibiotics, due to modifications (methylation) of 23S rRNA molecules by Erm methylase, which usually prevents the binding of all three structural classes. Two types of macrolide efflux have been described: msrA encodes a component of the efflux system in staphylococci that prevents the access of macrolides and streptogramin, while mefA/E encodes a transmembrane protein that leads to the efflux of only macrolides. Deactivation of macrolide antibiotics can be performed, that is, it can be induced either with the phosphorylation of 2'-hydroxyl (mph) or with the breaking of the macrocyclic lactone (esterase). Species can be characterized using conventional polymerase chain reaction (PCR) technology and/or resistance determinant sequencing.

The use of PCR technology in this application is described in J. Sutcliffe et al.: "Detection of Erythromycin-Resistant Determinants by PCR, Antimicrobial Agents and Chemotherapy", 40 (11), p. 2562-2566, (1966). The test is performed in microtiter vessels and interpreted according to "Performance Standards for Antimicrobial Disk Susceptibility Tests", 6th edition; Approved Standard, which is published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines; MIC (minimum inhibitory concentration) is used to compare species. Compounds were initially dissolved in dimethyl sulfoxide (DMSO) as a 40 mg/ml batch solution.

[image]

Experiment II was used as a test for activity against Pasteurella multocida, and Experiment III was used as a test for activity against Pasteurella haemolytica.

Experiment II

This experiment is based on a liquid dilution procedure on a microliter format. One colony of P. multocida (strain 59A067) was inoculated into 5 ml of brain infusion broth (BHI). The compounds to be tested were prepared by solubilizing 1 mg of the compound in 125 µl of dimethylsulfoxide (DMSO). Dilutions of the test compound were prepared using uninoculated BHI broth. Test compound concentrations ranging from 200 µg/ml to 0.098 µg/ml were used using two-fold serial dilutions. P. multocida inoculated with BHI was diluted with non-inoculated BHI broth to obtain a suspension of 104 cells per 200 µl. BHI cell suspensions were mixed with appropriate serial dilutions of the test compound and incubated at 37°C for 18 hours. The minimum inhibitory concentration (MIC) is equal to the concentration of the compound that shows 100% inhibition of the growth of P. multocida as determined by comparison with the uninoculated control.

Experiment III

This experiment is based on an agar dilution procedure using a Steers Replicator. Two to five colonies were isolated from the agar plate and inoculated into BHI broth, then incubated overnight at 37 °C with shaking (200 rpm). The following morning, 300 µl of fully grown P. Haemolytica preculture was inoculated into 3 ml of fresh BHI broth and incubated at 37 °C with shaking (200 rpm). Appropriate amounts of test compounds were dissolved in ethanol and two-fold dilution series were prepared. 2 ml of the appropriate serial dilution was mixed with 18 ml of melted BHI agar and solidified. When the inoculated P. haemolytica culture reaches 0.5 McFarland standard density, about 5 µl of the P. haemolytica culture is inoculated onto BHI agar plates containing various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 37 °C. Initial concentrations of the compound being tested range from 100 to 200 µg/ml. The MIC is equal to the concentration of the test compound that shows 100% inhibition of the growth of P. Haemolytica as determined by comparison with a non-inoculated control.

The in vivo activity of the compounds of formula (I) can be determined using conventional animal protection studies, which are well known to those skilled in the art and are usually performed in mice.

Mice were housed in cages (10 mice per cage) upon arrival, and were allowed to acclimate for at least 48 hours before being used. Animals were inoculated with 0.5 ml of 3 × 103 CFU/ml bacterial suspension (P. multocida species 59A006) intraperitoneally. Each experiment has at least three unmedicated control groups, including one infected with the 0.1X challenge dose and two infected with the 1X challenge dose; the 10X challenge dose data group can also be used. In general, all mice in a given trial can be treated within 30-90 minutes, especially if a multi-use syringe (such as a ® syringe) is used to administer the challenge. 30 minutes after the introduction of the challenger started, the treatment with the first compound was carried out. It may be necessary for a second person to start dosing if all animals are unable to receive the challenger at the end of 30 minutes. Methods of administration are subcutaneous or oral dosing. Subcutaneous doses were administered into the free skin at the back of the neck, while oral doses were administered using a feeding needle. In both cases, a volume of 0.2 ml per mouse is used. The compounds were applied at 30 minutes, at 4 hours and at 24 hours after introduction of the challenger. A control compound of known potency was applied in the same manner and was included in each test. The animals were observed during the day, and the number of surviving animals in each group was recorded. The P.multocida observation model continued for 96 hours (4 days) after introduction of the challenger.

The PD50 is the calculated dose at which the test compound protects 50% of a group of mice from mortality due to a bacterial infection that should be fatal in the absence of drug treatment.

The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as "active compounds") can be administered by the oral, parenteral, topical or rectal route in the treatment or prevention of bacterial or protozoan infections. In general, these compounds are most preferably administered in doses ranging from about 0.2 mg per kg of body weight per day (mg/kg/day) to about 200 mg/kg/day in single or divided doses (for example, from 1 to 4 doses per day), although it will be necessary to make certain variations depending on the species, weight and condition of the subject being treated and the specific method of application chosen. However, a dosage level in the range of about 4 mg/kg/day to about 50 mg/kg/day is most preferably used. Variations are always possible, depending on the type of mammal, fish or bird being treated and its individual response to the mentioned medication, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such application is made. In some cases, levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, doses higher than the upper limit may be used without causing adverse side effects, with the limitation that such higher doses are first divided into several small doses for administration during days.

The active compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents in the manner indicated above, and such administration may be performed in a single dose or in multiple doses. More precisely, the active compounds can be administered in a wide variety of different dosage forms, for example these can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, trochees, hard candies, powders, sprays, creams, ointments, suppositories, jellies , gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. However, oral pharmaceutical preparations may be suitably sweetened and/or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used together with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes. Solid preparations of a similar type can also be used as fillers in gelatin capsules; preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs for oral administration are desired, the active compound may be combined with various sweetening or flavoring agents, colorants or dyes, and if desired with emulsifying and/or suspending agents, and diluents such as water, ethanol, propylene glycol, glycerin and their various combinations.

For parenteral administration, solutions of the active compound either in peanut or sesame oil or in aqueous propyl glycol can be used. If necessary, aqueous solutions can be suitably buffered (preferably to a pH greater than 8), whereby the liquid diluent is first brought to isotonicity. These aqueous solutions are suitable for intravenous injection purposes. Oil solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. Obtaining all of these solutions under sterile conditions is readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

Additionally, the active compounds of the described invention can also be administered topically, which can be done using creams, jellies, gels, pastes, plasters, ointments, and the like, in accordance with standard pharmaceutical practice.

For use in animals, such as cattle or other domestic animals, the active compounds can be administered in animal feed, or orally as preparations that are applied when feeding animals.

The active compounds can also be administered in the form of liposomal delivery systems, such as unilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Active compounds can also be bound with soluble polymers that can be carriers of the desired drug. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenyl, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, active compounds can be attached to a class of biodegradable polymers used to achieve controlled drug release, for example polyacetic acid, polyglycolic acid, copolymers of polyacetic and polyglycolic acids, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

The examples given below illustrate specific embodiments of the invention, and the scope of the invention is not limited to those specifically shown examples.

Example 1

4'-acetyl-11-deoxy-11-hydrazo-6-O-methyl-erythromycin A, 11,12-carbamate

In a solution of 10,11-anhydro-2',4'-di-O-acetyl-12-O-imidazolylcarbonyl-6-O-methylerythromycin A (460 mg, 0.51 mmol) (obtained according to the procedures of Baker et al. .: "J. Org. Chem.", 53, p. 2340, (1988)), in MeCN at room temperature, anhydrous NH2NH2 (0.16 ml, 5.1 mmol) was added and the resulting solution was heated at 60 °C for 12 hours. The MeCN was removed in vacuo and brine and EtOAc were added, after which the aqueous layer was extracted with EtOAc (three times). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product is purified by flash silica gel chromatography (1.5% Et3N / 1.5% MeOH / 97% MeOBu-t) to give the title compound as a white solid (261 mg, 62%) and 4'-acetyl -10-epi-11-deoxy-11-hydrazo-6-O-methylerythromycin A, 11,12-carbamate as a white solid (38 mg, 10 %).

For the title compound 1H NMR (400 MHz, CDCl3) δ: 5.02 (1H, dd, J=1.6, 10.8 Hz); 4.94 (1H, d, J=4.8 Hz); 4.65 (1H, d, J=10.0 Hz); 4.53 (1H, d, 7=9.2 Hz); 4.33 (1H,m); 3.82-3.30 (m); 3.29 (3H, s); 3.20-3.00 (m); 3.00 (3H, s); 2.92-2.31 (m); 2.27 (6H, s); 2.08 (3H, s); 2.0-1.4 (m) and 0.82 (3H, t, J=7.6 Hz); MS: m/z 830 (M+H).

For 4'-acetyl-10-epi-11-deoxy-11-hydrazo-6-O-methylerythromycin A, 11,12-carbamate 1H NMR (400 MHz, CDCl3) δ: 5.05 (1H, dd, J= 4.4 Hz); 4.87 (1H, dd, J=1.6, 10.8 Hz); 4.64 (1H, d, J=10.0 Hz); 4.43 (1H, d, 7=7.6 Hz); 4.33 (1H,m); 3.84-3.32 (m); 3.30 (3H, s); 3.18 (3H, s); 3.2-2.3 (m); 2.23 (6H, s); 2.08 (3H, s); 1.62 (3H, s); 1.30 (3H, s); 0.97 (3H, d, J=6.8 Hz) and 0.84 (3H, t, J=7.2 Hz); MS: m/z 830 (M+H).

Example 2

11-deoxy-5-O-desosaminyl-11-hydrazo-6-O-methyl-erythronolide A, 11,12-carbamate

A solution of 4'-acetyl-11-deoxy-11-hydrazo-6-O-methylerythromycin A, 11,12-carbamate (40 mg, 0.048 mmol) in EtOH-2N HCl (1:2) was stirred at room temperature overnight , and the reaction mixture is poured into a cold solution of saturated NaHCO3. The aqueous layer is extracted with CHCl3 (3 times). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product is purified by flash silica gel chromatography (5% MeOH / 0.5% NH3•H2O / 94.5% CH2Cl2) to give the title compound as a white solid (26.1 mg, 86%).

1H NMR (400 MHz, CDCl 3 ) δ: 5.09 (1H, dd, J=2.4, 10.8 Hz); 4.45 (1H, s); 4.38 (1H, d, J=7.6 Hz); 3.9-3.0 (m); 2.95 (3H, s); 2.75-2.45 (m); 2.27 (6H, s); 2.0-1.4 (m); 1.40 (3H, s); 1.34 (3H, s); 1.24 (3H, d, J=6.8 Hz); 1.23 (3H, d, J=6.0 Hz); 1.12 (3H, d, J=7.2 Hz); 1.09 (3H, d, J=7.2 Hz); 1.07 (3H, d, J=6.8 Hz) and 0.80 (3H, t, J=7.6 Hz).

13 C NMR (100.6 MHz, CDCl 3 ) δ: 216.90; 175.69; 156.45; 106.65; 88,29; 81.46; 78.74; 78.36; 75.78; 70.63; 70.23; 65.71; 63.37; 49.30; 45.35; 44.66; 40.27 (2C); 39.57; 38.87; 36.07; 28,28; 22.01; 21,23; 18.88; 18,16; 15,19; 14,15; 13.74; 10,14; 8.22.

MS: m/z 629 (M+H).

Example 3

11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-6-O-methyl-erythronolide A, 11,12-carbamate

3- (4-quinolinyl)propionalide (0.57 g, 3.08 mmol), and the resulting solution was heated at 86 °C for 2 days. The EtOH was evaporated in vacuo to give the title compound as a white solid (1.84 g, 97 %).

1H NMR (400 MHz, CDCl 3 ) δ: 8.81 (1H, d, J=4.4 Hz); 8.09 (1H, d, J=5.2 Hz); 8.07 (1H, d, J=5.2 Hz); 7.69 (1H, t, J=8.4 Hz); 7.56 (1H, t, J=7.2 Hz); 7.29 (1H, d, J=4.0 Hz); 5.08 (1H, dd, J=2.0, 10.8 Hz); 4.53 (1H, s); 4.41 (1H, d, J=7.6 Hz); 4.2-3.2 (m); 2.99 (3H, s); 2.9-2.4 (m); 2.25 (6H, s); 2.0-1.5 (m); 1.48 (3H, s); 1.29 (3H, s); 1.30 (3H, d, J=6.4 Hz); 1.24 (3H, d, J=6.0 Hz); 1.15 (3H, d, J=6.4 Hz); 1.10 (3H, d, J=7.2 Hz); 1.07 (3H, d, J=6.4 Hz) and 0.87 (3H, t, J=7.2 Hz).

MS: m/z 794 (M+H).

Example 4

2'-acetyl-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-6-O-methyl-erythronolide A, 11,12-carbamate

In a solution of 11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-6-O-methylerythronolide A, 11,12-carbamate (2.07 g, 2.60 mmol) in CH2Cl2 (10 ml) was added acetic anhydride (0.49 ml, 5.20 mmol), and the resulting solution was stirred at room temperature for 5 hours. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and evaporated in vacuo to give the title compound as a white solid (1.79 g, 82 %).

1H NMR (400 MHz, CDCl 3 ) δ: 8.80 (1H, d, J=4.4 Hz); 8.08 (1H, d, J=8.4 Hz); 8.05 (1H, d, J=9.2 Hz); 8.01 (1H, t, J=4.8 Hz); 7.68 (1H, dt, J=1.2, 6.8 Hz); 7.55 (1H, dt, J=1.2, 6.8 Hz); 7.27 (1H, d, J=4.4 Hz); 5.02 (1H, dd, J=2.8, 10.0 Hz); 4.718 (1H, t, J=6.7 Hz); 4.40 (1H, s); 4.35 (1H, d, J=7.6 Hz); 4.19 (1H, d, J=8.0 Hz); 3.81 (1H, q, J=6.8 Hz); 3.6-2.4 (m); 2.71 (3H, s); 2.24 (6H, s); 1.9-1.5 (m); 1.55 (3H, s); 1.35 (3H, d, J=6.8 Hz); 1.33 (3H, s); 1.22 (3H, d, J=6.0 Hz); 1.14 (3H, d, J=7.6 Hz); 1.10 (3H, d, J=6.8 Hz); 1.06 (3H, d, J=6.4 Hz) and 0.87 (3H, t, J=7.2 Hz).

MS: m/z 837 (M+H).

Example 5

2'-acetyl-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-6-O-oxo-erythronolide A, 11,12-carbamate

In a solution of 2'-acetyl-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-6-O-methylerythronolide A, 11,12-carbamate (1.69 g, 2.02 mmol) in CH2Cl2 (16 ml) were added DMSO (1.85 ml, 8.06 mmol, 10 equiv), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDAC) (1.55 g, 8.06 mmol, 3.1 equivalent) and Py•TFA (1.56 g, 8.06 mmol, 3.1 equivalent), and the resulting suspension was stirred at room temperature for 2 hours. Saturated NaHCO3 solution was added, and the aqueous layer was extracted with CH2Cl2 (three times). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and evaporated under vacuum. The crude product is purified by flash silica gel chromatography (5% MeOH / 0.5% NH3•H2O / 94.5% CH2Cl2) to give the title compound as a white solid (1.59 g, 94%).

1H NMR (400 MHz, CDCl 3 ) δ: 8.79 (1H, d, J=3.6 Hz); 8.08 (1H, d, J=8.8 Hz); 8.05 (1H, d, J=8.4 Hz); 8.00 (1H, t, J=4.8 Hz); 7.69 (1H, t, J=8.4 Hz); 7.55 (1H, t, J=7.2 Hz); 7.27 (1H, d, J=4.4 Hz); 5.03 (1H, dd, J=2.4, 10.0 Hz); 4.70 (1H, dd, J=7.6, 10.4 Hz); 4.39 (1H, s); 4.34 (1H, d, J=7.6 Hz); 4.18 (1H, d, J=8.0 Hz); 3.82 (1H, q, J=6.8 Hz); 3.6-1.6 (m); 2.71 (3H, s); 2.22 (6H, s); 2.03 (3H, s); 1.54 (3H, s); 1.33 (3H, d, J=6.4 Hz); 1.28 (3H, s); 1.21 (3H, d, J=6.4 Hz); 1.14 (3H, d, J=7.6 Hz); 1.09 (3H, d, J=6.8 Hz); 1.06 (3H, d, J=6.8 Hz); 0.87 (3H, t, J=7.2 Hz).

MS: m/z 836 (M+H).

Example 6

11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate

In solution, 2'-acetyl-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (1 .59 g, 1.90 mmol) in MeOH (25 mL) at room temperature was added NaBH3CN (359 mg, 5.70 mmol, 3 equiv) followed by the addition of HOAc (0.65 mL, 11.4 mmol, 6 equivalent), and the resulting reaction mixture is stirred at room temperature overnight. The MeOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and evaporated under vacuum. The residue was dissolved in MeOH (50 mL), and the solution was heated under reflux for 1 hour. The MeOH is then removed in vacuo and the crude product is purified by flash silica gel chromatography (5% MeOH / 0.5% NH3•H2O / 94.5% CH2Cl2) to afford the title compound as a white solid (1.13 g, 75 %).

1H NMR (400 MHz, CDCl 3 ) δ: 8.75 (1H, d, J=4.27 Hz); 8.07 (2H, t, J=9.4 Hz); 7.64 (1H, dt, J=1.6, 6.8 Hz); 7.50 (1H, dt, J=1.6, 7.2 Hz); 7.26 (1H, d, J=4.4 Hz); 5.47 (1H, t, J=3.6 Hz); 4.98 (1H, d, J=10.8 Hz); 4.26 (1H, s); 4.24 (1H, s); 3.84 (1H, q, J=6.8 Hz); 3.71 (1H, s); 3.8-2.7 (m); 2.62 (3H, s); 2.6-2.3 (m); 2.22 (6H, s); 2.2-1.5 (m); 1.44 (3H, s); 1.33 (3H, d, J=6.8 Hz); 1.31 (3H, s); 1.29 (3H, d, J=7.6 Hz); 1.21 (3H, d, J=6.0 Hz); 1.16 (3H, d, J=6.0 Hz); 1.04 (3H, d, J=6.8 Hz) and 0.78 (3H, t, J=7.2 Hz).

13 C NMR (100.6 MHz, CDCl 3 ) δ (attached H): 217.82 (0); 203.63 (0); 169.72 (0); 156.10 (0); 150.18 (1); 148.20 (2C, 0); 130.05 (1); 128.85 (1); 127.58 (0); 126.19 (1); 123.81 (1); 120.97 (1); 103.96 (1); 80.69 (0); 79.37 (1); 78.12 (0); 77.35 (1); 70.33 (1); 69.63 (1); 65.84 (1); 58.14 (1); 51.04 (1); 50.13 (3); 48.41 (2); 47.31 (1); 44.55 (1); 40.19 (2C, s); 39.60 (2C, 2 and 1); 29.49 (2); 28.47 (2); 28.14 (2); 22.03 (2); 21.14 (3); 19.82 (3); 18.50 (3); 15.31 (3); 14.55 (3); 14.38 (3); 14.21 (3) and 10.35 (3).

MS: m/z 797 (M+H).

Example 7

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-hydroxymino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate

Procedure 1

In a solution of 11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (654 mg, 0.82 mmol) in i-PrOH (8.0 mL) was added NH2OH•HCl (855 mg, 12.3 mmol, 15 equiv), and the reaction mixture was heated at 90 °C for 6 days. The i-PrOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product is purified by preparative TLC (10 % MeOH / 1 % NH3•H2O / 89 % CH2Cl2) to give the title compound as a white solid (224 mg, 34 %) and to isolate the starting material (107 mg, 16 %).

1H NMR (400 MHz, CDCl 3 ) δ: 10.85 (1H, br s); 8.39 (1H, d, J=4.4 Hz); 8.00 (2H, d, J=8.4 Hz); 7.90 (1H, d, J=8.0 Hz); 7.60 (1H, t, J=7.2 Hz); 7.42 (1H, t, J=7.6 Hz); 6.82 (1H, d, J=4.8 Hz); 5.05 (1H, dd, J=2.0, 10.8 Hz); 4.30 (1H, dd, J=5.6, 7.2 Hz); 3.89 (1H, q, J=6.4 Hz); 3.92 (1H, s); 3.55 (1H, m); 3.27 (1H, m); 3.15-2.50 (m); 2.83 (3H, s); 2.35 (6H, s); 1.95 (1H, m); 1.8-1.2 (m); 1.55 (3H, s); 1.49 (3H, s); 1.35 (3H, d, J=6.8 Hz); 1.29 (3H, d, J=7.6 Hz); 1.26 (3H, d, J=6.0 Hz); 1.15 (3H, d, J=6.8 Hz); 1.03 (3H, d, J=6.8 Hz) and 0.825 (3H, t, J=7.2 Hz).

13 C NMR (100.6 MHz, CDCl 3 ) δ (attached H): 203.73 (0); 169.85 (0); 166.52 (0); 156.35 (0); 149.22 (1); 147.06 (0); 129.35 (1); 128.85 (1); 127.36 (0); 126.41 (1); 123.77 (1); 120.24 (1); 103.91 (1); 80.28 (0); 79.77 (1); 78.66 (0); 77.37 (1); 70.34 (1); 69.40 (1); 65.95 (1); 59.68 (1); 51.16 (1); 50.52 (3); 48.08 (2); 47.52 (1); 40.26 (2C, 3); 38.26 (2); 33.66 (1); 29.40 (2); 28.51 (2); 27.93 (2); 25.59 (1); 22.17 (2); 21.18 (3); 20.09 (3); 19.15 (3); 17.40 (3); 15.37 (3); 14.52 (3); 14.36 (3) and 10.44 (3).

MS: m/z 812 (M+H).

Procedure 2

In solution 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12- carbamate (186 mg, 0.23 mmol) which was obtained according to the procedures described in example 17, HOAc (212 µl, 3.7 mmol) and NaBH3CN (158 mg, 2.3 mmol) were added in methanol, and the obtained the mixture is stirred at room temperature for 12 hours. The MeOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product is purified by flash silica gel chromatography (5% MeOH / 0.5% NH3•H2O / 94.5% CH2Cl2) to give the title compound as a white solid (114 mg, 61%).

Example 8

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

Procedure 1

In a solution of 11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (50 mg, 0.063 mmol) NH2OMe•HCl (26 mg, 0.31 mmol, 5 equiv) was added to i-PrOH (1.0 mL), and the reaction mixture was heated at 90 °C for 3 days. The i-PrOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by preparative TLC (10% MeOH / 1% NH3•H2O / 89% CH2Cl2) to give the title compound as a white solid (27 mg, 52%) and to isolate some starting material.

1H NMR (400 MHz, CDCl 3 ) δ: 8.75 (1H, d, J=4.4 Hz); 8.12 (1H, d, J=8.4 Hz); 8.06 (2H, d, J=8.8 Hz); 7.65 (1H, t, J=6.8 Hz); 7.50 (1H, t, J=6.8 Hz); 7.27 (1H, d, J=4.4 Hz); 6.04 (1H, no s); 5.01 (1H, d, J=9.6 Hz); 4.30-1.4 (m); 3.86 (1H, q, J=6.8 Hz); 3.70 (3H, s); 2.66 (3H, s); 2.31 (6H, s); 1.45 (3H, s); 1.37 (3H, s); 1.33 (3H, d, J=6.8 Hz); 1.27 (3H, d, J=7.2 Hz); 1.24 (3H, d, J=6.0 Hz); 1.10 (3H, d, J=6.4 Hz); 0.98 (3H, d, J=6.8 Hz) and 0.77 (3H, t, J=7.6 Hz).

MS: m/z 826 (M+H).

Procedure 2

The title compound is obtained from 9-deoxo-11-deoxy-5-O-desosaminyl-11-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate and 3-quinolin-4-yl -propionaldehyde following the procedures described in example 11.

Example 9

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-benzoxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

In a solution of 11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (40 mg, 0.050 mmol) NH2OBn•HCl (32 mg, 0.20 mmol) was added to i-PrOH (1.0 ml) and the reaction mixture was heated at 90 °C for 3 days. The i-PrOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by preparative TLC (10% MeOH / 1% NH3•H2O / 89% CH2Cl2) to give the title compound as a white solid (10 mg, 22%) and to isolate some starting material.

1H NMR (400 MHz, CDCl 3 ) δ: 8.75 (1H, d, J=4.4 Hz); 8.10 (1H, d, J=8.4 Hz); 8.07 (1H, d, J=8.4 Hz); 7.65 (1H, t, J=6.8 Hz); 7.49 (1H, t, J=8.4 Hz); 7.30 (6H, m); 5.82 (1H, no s); 4.99 (1H, d, J=8.0 Hz); 4.95 (1H, d, J=12.4 Hz, AB); 4.85 (1H, d, J=12.4 Hz, AB); 4.3-1.4 (m); 3.86 (1H, q, J=6.8 Hz); 2.67 (3H, s); 2.30 (6H, s); 1.44 (3H, s); 1.40 (3H, s); 1.33 (3H, d, J=6.8 Hz); 1.28 (3H, d, J=7.6 Hz); 1.25 (3H, d, J=6.0 Hz); 1.07 (3H, d, J=7.2 Hz); 0.95 (3H, d, J=6.8 Hz) and 0.75 (3H, t, J=7.2 Hz).

MS: m/z 902 (M+H).

Example 10

9-deoxo-11-deoxy-5-O-desosaminyl-11-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate

To a solution of 11-deoxy-5-O-desosaminyl-11-hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (600 mg, 0.96 mmol) in EtOH (9.0 ml) was added NH2OMe•HCl (319 mg, 3.83 mmol, 4.0 equiv) was added, and the reaction mixture was heated at 80 °C for 2 days. EtOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give the compound as a white solid (602 mg).

1H NMR (400 MHz, CDCl 3 ) δ: 3.77 (3H, s); 2.68 (3H, s); 2.25 (6H, s); 1.43 (3H, s); 1.38 (3H, s); 1.33 (3H, d, J=7.2 Hz); 1.27 (3H, d, J=7.6 Hz); 1.23 (3H, d, J=6.0 Hz); 1.13 (3H, d, J=6.8 Hz); 0.98 (3H, d, J=6.8 Hz) and 0.83 (3H, t, J=7.6 Hz).

MS: m/z 657 (M+H).

Example 11

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-pyridin-3-yl-imidazol-1-yl)-propyl)-hydrazo-9-methoxyimino-6-O

-methyl-3-oxoerythronolide A, 11,12-carbamate

In a solution of 9-deoxo-11-deoxy-5-O-desosaminyl-11-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (300 mg, 0.45 mmol) in 3-(4-pyridin-3-yl-imidazol-1-yl)-propionaldehyde (100 mg, 0.40 mmol, 1.1 equivalent) was added to toluene (4.0 ml) and the reaction mixture was heated to 90 ° C during 3 days. The toluene was removed in vacuo and the residue was dissolved in MeOH (4.0 mL). HOAc (0.39 mL, 6.8 mmol) and NaBH 3 CN (427 mg, 6.8 mmol) were added, and the resulting solution was stirred at room temperature for 14 h. The MeOH was removed in vacuo and saturated NaHCO3 was added to the residue, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by preparative TLC (10% MeOH / 1% NH3•H2O / 89% CH2Cl2) to give the title compound as a white solid.

1H NMR (400 MHz, CDCl 3 ) δ: 8.94 (1H, s); 8.42 (1H); 8.03 (1H); 7.58 (1H, s); 7.36 (1H, s); 6.11 (1H, s); 3.69 (3H, m); 2.64 (3H, s); 2.23 (6H, s); 1.45 (3H, s); 1.36 (3H, s); 1.30 (3H, d, J=5.6 Hz); 1.26 (3H, d, J=6.8 Hz); 1.21 (3H, d, J=4.8 Hz); 1.09 (3H, d, J=6.8 Hz); 0.97 (3H, d, J=6.4 Hz) and 0.80 (3H, t, J=6.4 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.41; 170.01; 167.63; 156.73; 147.56; 146.40; 138.94; 138.13; 131.85; 130.31; 123.47; 115.12; 103.99; 81.36; 79.51; 78.51; 77.27; 70.33; 69.58; 65.84; 61.30; 59.24; 51.06; 50.40; 47.37; 44.39; 44.35; 40.23 (2C); 38,21; 33.86; 29,28; 28,12; 26.48; 22,11; 21:18; 19.91; 18.97; 17.45; 15,19; 14.49; 14:33 and 10:53.

MS: m/z 842 (M+H).

Example 12

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(imidazo(4,5-b)pyridin-3-yl)-propyl)-hydrazo-9-methoxyimino-6-O-methyl

-3-oxoerythronolide A, 11,12-carbamate

In a solution of 9-deoxo-11-deoxy-5-O-desosaminyl-11-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (2.0 g, 3.05 mmol ) in toluene (30 ml) was added 3-(imidazo(4,5-b)pyridin-3-yl)-propioaldehyde (910 mg, 4.26 mmol, 1.4 equivalent), and the reaction mixture was heated to 90 °C during 18 hours. The toluene was removed in vacuo and the residue was dissolved in MeOH (30 mL). HOAc (2.8 ml, 48.72 mmol) and NaBH3CN (1.91 g, 30.45 mmol) were added, and the resulting solution was stirred at room temperature for 14 hours. The MeOH was removed in vacuo and saturated NaHCO3 was added to the residue, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by preparative TLC (10% MeOH / 1% NH3•H2O / 89% CH2Cl2) to give the title compound as a white solid.

1H NMR (400 MHz, CDCl 3 ) δ: 8.35 (1H); 8.22 (1H, s); 8.02 (1H); 7.20 (1H); 7.36 (1H, s); 6.10 (1H, no t); 3.47 (3H, s); 2.62 (3H, s); 2.24 (6H, s); 1.46 (3H, s); 1.37 (3H, s); 1.30 (3H, d, J=6.8 Hz); 1.27 (3H, d, J=7.6 Hz); 1.22 (3H, d, J=6.0 Hz); 1.12 (3H, d, J=6.8 Hz); 0.99 (3H, d, J=7.2 Hz) and 0.84 (3H, t, J=7.6 Hz).

MS: m/z 816 (M+H).

Example 13

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-imidazol-1-yl)-propyl)-hydrazo-9-methoxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

In a solution of 9-deoxo-11-deoxy-5-O-desosaminyl-11-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (1.37 g, 2.09 mmol ) in toluene (14 ml), 3-(4-phenyl-imidazol-1-yl)-propioaldehyde (583 mg, 9.92 mmol, 1.4 equivalent) was added and the reaction mixture was heated at 90 °C for 18 hours . The toluene was removed in vacuo and the residue was dissolved in MeOH (20 mL). HOAc (1.8 ml, 31.35 mmol) and NaBH3CN (1.97 g, 31.35 mmol) were added, and the resulting solution was stirred at room temperature for 14 hours. The MeOH was removed in vacuo and saturated NaHCO3 was added to the residue, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by preparative TLC (10% MeOH-1% NH3•H2O-89% CH2Cl2) to give the title compound as a white solid.

1H NMR (400 MHz, CDCl 3 ) δ: 8.35 (1H); 8.22 (1H, s); 8.02 (1H); 7.20 (1H); 7.36 (1H, s); 6.10 (1H, no t); 3.69 (3H, s); 2.66 (3H, s); 2.26 (6H, s); 1.46 (3H, s); 1.37 (3H, s); 1.32 (3H, d, J=6.8 Hz); 1.27 (3H, d, J=7.6 Hz); 1.22 (3H, d, J=6.0 Hz); 1.11 (3H, d, J=7.2 Hz); 0.98 (3H, d, J=7.2 Hz) and 0.83 (3H, t, J=7.2 Hz).

MS: m/z 841 (M+H).

Example 14

9-deoxo-11-deoxy-5-O-desosaminyl-10-epi-11-hydrazo-9-benzoxiimino-6-O-methyl-3-oxoerythronolide A, 11,12

- carbamate

In a solution of 11-deoxy-5-O-desosaminyl-10-epi-11-hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (202 mg, 0.322 mmol) in MeOH (3.0 mL ) was added NH2Bn•HCl (225 mg, 1.41 mmol, 4.4 equiv), and the reaction mixture was heated to 72 °C for 16 h. The MeOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by preparative TLC (10% MeOH / 1% NH3•H2O / 89% CH2Cl2) to give the title compound as a white solid.

1H NMR (400 MHz, CDCl 3 ) δ: 8.25 (5H, m); 5.39 (4H, no s); 5.09 (1H, d, J=12.8 Hz, AB); 4.99 (1H, d, J=12.8 Hz, AB); 4.93 (1H, d, J=3.2, 9.2 Hz); 4.30 (1H, d, J=7.2 Hz); 3.98 (1H, d, J=10.8 Hz); 3.54 (1H, q, J=6.8 Hz); 3.9-1.3 (m); 2.75 (3H, s); 2.27 (6H, s); 2.02 (3H, d, J=6.8 Hz); 1.30 (3H, s); 1.27 (3H, d, J=7.2 Hz); 1.22 (3H, s); 1.21 (3H, d, J=6.8 Hz); 1.20 (3H, d, J=6.8 Hz); 1.09 (3H, d, J=7.2 Hz) and 0.814 (3H, t, J=7.6 Hz).

MS: m/z 733 (M+H).

Example 15

9-deoxo-11-deoxy-5-O-desosaminyl-10-epi-11-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12

- carbamate

In a solution of 11-deoxy-5-O-desosaminyl-10-epi-11-hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (499 mg, 0.795 mmol) in i-PrOH (7, 0 ml) was added NH2OH•HCl (579 mg, 8.33 mmol, 10.5 equiv), and the reaction mixture was heated at 80 °C for 3 days. The i-PrOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product is purified by preparative TLC (10% MeOH / 1% NH3•H2O / 89% CH2Cl2) to give a 3:2 mixture of the title compound as a white solid (157 mg, 31%).

1H NMR (400 MHz, CDCl3) δ: for the isomer obtained in larger amount: 2.77 (3H, with 6-OMe); 2.26 (6H, s, NMe2); 0.84 (3H, t, J=7.0 Hz, 15-Me); MS: m/z 610 (M+H).

1H NMR (400 MHz, CDCl3) δ: for the isomer obtained in a smaller amount: 2.68 (3H, with 6-OMe); 2.25 (6H, s, NMe2); 0.81 (3H, t, J=7.0 Hz, 15-Me); MS: m/z 610 (M+H).

Example 16

9-deoxo-11-deoxy-5-O-desosaminyl-11-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate

To a solution of 11-deoxy-5-O-desosaminyl-11-hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (20 g, 31.8 mmol) in EtOH (210 ml) was added NH2OH •HCl (33.1 g, 477 mmol, 15 equivalent) and pyridine (38.4 ml, 477 mmol, 15 equivalent), and the resulting solution was heated to 80 °C for 38 hours. EtOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by preparative TLC (10% MeOH / 1% NH3•H2O / 89% CH2Cl2) to give the title compound as a white solid (7.3 g).

1H NMR (400 MHz, CDCl 3 ) δ: 9.81 (1H, no.s); 2.67 (3H, s); 2.57 (1H, q, J=6.8 Hz); 2.25 (6H, s); 1.47 (3H, s); 1.32 (3H, d, J=6.8 Hz); 1.25 (3H, d, J=7.6 Hz); 1.21 (3H, d, J=6.4 Hz); 1.11 (3H, d, J=6.8 Hz); 0.9 (3H, d, J=7.2 Hz); 0.83 (3H, t, J=7.2 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.81; 169.80; 165.97; 156.68; 103.91; 81.53; 79.85; 78.49; 76.74; 70.35; 69.48; 65.85; 64.33; 51.10; 49.66; 47.73; 40.24; 38,42; 33.73; 28,19; 25.55; 22,11; 21.15; 19.98; 18.64; 16.96; 15.68; 14.25; 13.71 and 10.39.

MS: m/z 643 (M+H).

Example 17

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

In a solution of 9-deoxo-11-deoxy-5-O-desosaminyl-11-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (150 g, 0.23 mmol) in 3-(4-quinolinyl)propionaldehyde (85 mg, 0.46 mmol) was added to anhydrous toluene (2.30 mL), and the resulting solution was heated at 90 °C for 18 h. Toluene is removed in vacuo and the crude product is purified by flash chromatography (5% MeOH / 0.5% NH3•H2O / 94.5% CH2Cl2) to give the title compound.

1H NMR (400 MHz, CDCl 3 ) δ: 2.84 (3H, s); 2.30 (6H, s); 1.58 (3H, s); 1.54 (3H, s); 1.34 (3H, d, J=6.8 Hz); 1.32 (3H, d, J=7.2 Hz); 1.28 (3H, d, J=6.0 Hz); 1.25 (3H, d, J=6.0 Hz); 1.05 (3H, d, J=7.2 Hz); 0.86 (3H, t, J=7.2 Hz).

MS: m/z 810 (M+H).

Example 18

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzoimidazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

In a solution of 9-deoxo-11-deoxy-5-O-desosaminyl-11-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (100 g, 016 mmol) in anhydrous toluene (1.6 ml) was added 3-(benzoimidazol-1-yl)propionaldehyde (62 mg, 0.36 mmol), and the resulting solution was heated at 90 °C for 18 hours. The toluene was removed in vacuo and the crude product was dissolved in methanol (1.5 mL). HOAc (137 µl, 2.4 mmol) and NaBH3CN (103 mg, 1.5 mmol) were added to this solution, and the resulting mixture was stirred at room temperature for 12 hours. The MeOH was removed in vacuo and the residue was dissolved in CH2Cl2. Saturated NaHCO3 solution was added, the aqueous layer was extracted with CH2Cl2 (three times), and the combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product is purified by preparative TLC (10% MeOH / 1% NH3•H2O / 89% CH2Cl2) to give the title compound as a white solid (57 mg, 46%).

1H NMR (400 MHz, CDCl 3 ) δ: 11.00 (1H, no.s); 2.71 (3H, s); 2.30 (6H, s); 1.49 (3H, s); 1.47 (3H, s); 1.34 (3H, d, J=6.8 Hz); 1.28 (3H, d, J=7.6 Hz); 1.23 (3H, d, J=6.0 Hz); 1.11 (3H, d, J=7.2 Hz); 0.99 (3H, d, J=6.8 Hz) and 0.824 (3H, t, J=7.2 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.45; 169.92; 166.21; 156.74; 143.31; 142.85; 133.53; 122.90; 122.12; 119.47; 110.23; 103.93; 81.33; 79.87; 78.59; 77.24; 70.29; 69.38; 65.97; 59.68; 51.09; 50.62; 47.45; 44,45; 42.34; 40.26; 38.23; 33.59; 28.49; 27.40; 25.55; 22:18; 21.15; 20.10; 19,11; 17.32; 15,28; 14.53; 14.39 and 10.51.

MS: m/z 801 (M+H).

The following compounds are prepared from 9-deoxo-11-deoxy-5-O-desosaminyl-11-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A 11,12-carbamate and the corresponding aldehyde using the procedures described above .

Example 19

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-imidazol-1-yl)-propyl)-hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 2.69 (3H, s); 2.29 (6H, s); 1.49 (3H, s); 1.47 (3H, s); 1.32 (3H, d, J=6.8 Hz); 1.27 (3H, d, J=7.6 Hz); 1.24 (3H, d, J=6.0 Hz); 1.10 (3H, d, J=6.8 Hz); 1.00 (3H, d, J=6.8 Hz) and 0.83 (3H, t, J=7.2 Hz).

MS: m/z 801 (M+H).

Example 20

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-2-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 9.95 (1H, br, s); 1.44 (3H, s); 1.39 (3H, s); 1.25 (6H, d, J=6.8 Hz); 1.23 (3H, d, J=6.0 Hz); 1.09 (3H, d, J=6.8 Hz); 1.03 (3H, d, J=6.8 Hz) and 0.81 (3H, t, J=7.6 Hz).

MS: m/z 802 (M+H).

Example 21

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-1-yl)-propyl)-hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 9.02 (1H, br, s); 6.23 (1H, no, s); 2.58 (3H, s); 2.32 (6H, s); 1.49 (3H, s); 1.47 (3H, s); 1.29 (3H, d, J=6.8 Hz); 1.26 (3H, d, J=7.6 Hz); 1.23 (3H, d, J=6.0 Hz); 1.10 (3H, d, J=6.8 Hz); 1.01 (3H, d, J=6.8 Hz) and 0.81 (3H, t, J=7.2 Hz).

MS: m/z 802 (M+H).

Example 22

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-phenylpropyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronalide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 9.59 (1H, no.s); 7.10 (5H, m); 6.55 (1H, no, s); 2.67 (3H, s); 2.24 (6H, s); 1.43 (6H, s); 1.33 (3H, d, J=6.8 Hz); 1.25 (3H, d, J=7.2 Hz); 1.21 (3H, d, J=6.0 Hz); 1.00 (3H, d, J=6.8 Hz); 0.92 (3H, d, J=6.4 Hz) and 0.824 (3H, t, J=7.2 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.70; 169.59; 166.73; 156.24; 142.12; 128.42 (2C); 128.20 (2C); 125.62; 103.94; 81.35; 79.63; 78.56; 77.11; 70.36; 69.48; 65.87; 59.50; 51.13; 50.40; 48.02; 47.52; 40.24 (2C); 38,21; 33.60; 33,14; 29.77; 28,21; 25.57; 22,19; 21.15; 20:13; 19.05; 17,13; 15.41; 14.46; 14.29 and 10.49.

MS: m/z 761 (M+H).

Example 23

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-hydroxyphenyl)-propyl)-hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 6.91 (2H); 6.68 (2H); 6.43 (1H, no, s); 2.67 (3H, s); 2.30 (6H, s); 1.44 (3H, s); 1.43 (3H, s); 1.33 (3H, d, J=6.8 Hz); 1.25 (3H, d, J=7.2 Hz); 1.21 (3H, d, J=6.0 Hz); 1.01 (3H, d, J=6.8 Hz); 0.92 (3H, d, J=6.4 Hz) and 0.80 (3H, t, J=7.2 Hz).

MS: m/z 778 (M+H).

Example 24

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-methoxyphenyl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 9.38 (1H, no.s); 7.04 (2H, d, J=8.45 Hz); 6.74 (2H, d, J=8.4 Hz); 6.44 (1H, no, s); 3.74 (3H, s); 2.67 (3H, s); 2.30 (6H, s); 1.44 (6H, s); 1.33 (3H, d, J=6.8 Hz); 1.25 (3H, d, J=7.6 Hz); 1.22 (3H, d, J=6.0 Hz); 1.01 (3H, d, J=6.8 Hz); 0.93 (3H, d, J=6.8 Hz) and 0.82 (3H, t, J=7.2 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.71; 169.58; 167.06; 157.64; 156.30; 134.23; 129.29 (2C); 113.68 (2C); 103.84; 81.33; 79.61; 78.51; 77.16; 70.27; 69.34; 65.98; 59.51; 55.19; 51.12; 50.44; 47.95; 40.26 (2C); 38,19; 33.64; 32.29; 30.06; 28.46; 25.55; 22,19; 21:12; 20.09; 19.05; 17,17; 15.34; 14.49; 14.33 and 10.49.

MS: m/z 792 (M+H).

Example 25

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(2-methoxyphenyl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 8.68 (1H, no.s); 7.13 (2H); 6.82 (2H); 3.80 (3H, s); 2.68 (3H, s); 2.30 (6H, s); 1.45 (6H, s); 1.43 (3H, s); 1.32 (3H, d, J=6.8 Hz); 1.26 (3H, d, J=7.6 Hz); 1.22 (3H, d, J=6.4 Hz); 1.06 (3H, d, J=6.8 Hz); 0.98 (3H, d, J=6.4 Hz) and 0.83 (3H, t, J=7.2 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.78; 169.59; 167.39; 157.04; 156.14; 130.36; 129.96; 120.82; 110.49; 103.86; 81.19; 79.16; 78.42; 77.24; 70.27; 69.37; 65.94; 59.88; 55,54; 51.10; 50.56; 48.26; 47.34; 40.24 (2C); 38.22; 33.70; 28.44; 27.83; 27.45; 25.58; 22,19; 21:13; 20.01; 19.07; 17.29; 15,21; 14.50; 14.43 and 10.37.

MS: m/z 792 (M+H).

Example 26

9-deoxo-11-deoxy-5-O-desosaminyl-11-(benzyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12

- carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 7.95 (1H, br, s); 6.23 (1H, no, s); 2.88 (3H, s); 2.29 (6H, s); 1.51 (3H, s); 1.44 (3H, s); 1.36 (3H, d, J=6.8 Hz); 1.29 (3H, d, J=7.6 Hz); 1.25 (3H, d, J=6.0 Hz); 1.05 (3H, d, J=6.8 Hz); 0.97 (3H, d, J=7.2 Hz) and 0.75 (3H, t, J=7.6 Hz).

MS: m/z 733 (M+H).

Example 27

9-deoxo-11-deoxy-5-O-desosaminyl-11-(pyridin-4-yl-methyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 8.07 (2H); 7.25 (2H); 6.39 (1H, no, s); 2.87 (3H, s); 2.27 (6H, s); 1.54 (3H, s); 1.46 (3H, s); 1.34 (3H, d, J=6.8 Hz); 1.29 (3H, d, J=7.2 Hz); 1.24 (3H, d, J=6.0 Hz); 1.13 (3H, d, J=6.8 Hz); 1.01 (3H, d, J=7.2 Hz) and 0.76 (3H, t, J=7.2 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.72; 169.91; 166.50; 155.76; 148.16 (2C); 147.70; 123.71 (2C); 103.99; 81.17; 79.75; 78.71; 77.26; 70.34; 69.50; 65.92; 60.30; 51.69; 51.15; 50.74; 47.62; 40.26 (2C); 38.25; 33.69; 28,29; 25.54; 22.02; 21:16; 20,16; 19,14; 17.36; 15.42; 14.50; 14.29 and 10.27.

MS: m/z 733 (M+H).

Example 28

9-deoxo-11-deoxy-5-O-desosaminyl-11-3-(pyridin-4-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 11.62 (1H, s); 8.24 (2H); 6.91 (2H); 6.20 (1H, no, s); 2.76 (3H, s); 2.31 (6H, s); 1.51 (3H, s); 1.46 (3H, s); 1.33 (3H, d, J=6.4 Hz); 1.27 (3H, d, J=7.2 Hz); 1.23 (3H, d, J=6.0 Hz); 1.10 (3H, d, J=6.8 Hz); 1.00 (3H, d, J=6.8 Hz) and 0.83 (3H, t, J=7.2 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.71; 169.78; 166.30; 156.35; 152.45; 124.10 (2C); 124.10 (2C); 103.86; 79.71; 78.59; 77.24; 70.27; 69.34; 65.98; 59.50; 51.15; 50.44; 47.55 (2C); 40.27 (2C); 38,21; 33.60; 32.50; 28.54; 27.90; 25.51; 22:14; 21:13; 20,11; 19,11; 17.33; 15.42; 14.48; 14.32 and 10.44.

MS: m/z 762 (M+H).

Example 29

9-deoxo-11-deoxy-5-O-desosaminyl-11-3-(pyridin-3-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 10.96 (1H, s); 8.30 (1H, d, J=4.4 Hz); 8.21 (1H, s); 7.40 (1H, d, J=8.0 Hz); 7.10 (1H, dd, J=5.2 and 7.6 Hz); 6.16 (1H, no, s); 2.70 (3H, s); 2.27 (6H, s); 1.48 (3H, s); 1.44 (3H, s); 1.31 (3H, d, J=7.2 Hz); 1.25 (3H, d, J=7.6 Hz); 1.21 (3H, d, J=6.0 Hz); 1.06 (3H, d, J=6.8 Hz); 0.96 (3H, d, J=6.8 Hz) and 0.80 (3H, t, J=7.6 Hz).

MS: m/z 762 (M+H).

Example 30

9-deoxo-11-deoxy-5-O-desosaminyl-11-(phenylethyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12

- carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 7.25 (3H, s); 2.59 (3H, s); 2.28 (6H, s); 1.40 (3H, s); 1.32 (3H, d, J=6.8 Hz); 1.30 (3H, s); 1.25 (3H, d, J=7.6 Hz); 1.22 (3H, d, J=6.0 Hz); 0.98 (3H, d, J=6.8 Hz); 0.88 (3H, d, J=6.8 Hz) and 0.83 (3H, t, J=7.6 Hz).

MS: m/z 747 (M+H).

Example 31

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-methoxyphenyl)(1,2,4)oxadiazol-5-yl)-propyl)hydrazo-9-hydroxyimino

-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 9.65 (1H, br, s); 7.87 (2H, d, J=8.4 Hz); 6.92 (2H, d, J=9.2 Hz); 6.16 (1H, no, s); 3.80 (3H, s); 2.46 (3H, s); 2.24 (6H, s); 1.03 (3H, d, J=7.2 Hz); 0.96 (3H, d, J=7.2 Hz); and 0.81 (3H, t, J=7.2 Hz).

MS: m/z 859 (M+H).

Example 32

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-chlorophenyl)(1,2,4)oxadiazol-5-yl)-propyl)hydrazo-9-hydroxyimino-6

-O-methyl-3-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 7.89 (2H, d, J=8.8 Hz); 7.39 (2H, d, J=8.8 Hz); 6.20 (1H, no, s); 2.49 (3H, s); 2.24 (6H, s); 1.42 (3H, s); 1.03 (3H, d, J=7.2 Hz); 0.96 (3H, d, J=6.8 Hz); and 0.82 (3H, t, J=7.2 Hz).

MS: m/z 863 (M+H).

Example 33

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 8.63 (1H, br, s); 8.02 (1H); 7.28 (1H); 7.04 (1H); 6.89 (1H); 6.23 (1H, no, s); 2.60 (3H, s); 2.30 (6H, s); 1.44 (3H, s); 1.39 (3H, s); 1.34 (3H, d, J=6.8 Hz); 1.25 (3H, d, J=7.6 Hz); 1.22 (3H, d, J=6.4 Hz); 1.02 (3H, d, J=7.2 Hz); 0.92 (3H, d, J=6.8 Hz) and 0.82 (3H, t, J=7.6 Hz), MS: m/z 800 (M+H).

Example 34

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 10.53 (1H, br, s); 7.91 (1H); 7.68 (1H); 7.44 (1H); 7.26 (1H); 7.12 (1H); 6.49 (1H, no, s); 2.54 (3H, s); 2.25 (6H, s); 1.48 (3H, s); 1.44 (3H, s); 1.08 (3H, d, J=6.8 Hz); 1.02 (3H, d, J=7.2 Hz) and 0.79 (3H, t, J=7.2 Hz).

MS: m/z 801 (M+H).

Example 35

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(5-phenyl-1H-pyrrol-2-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 9.36 (1H, br, s); 7.49 (1H); 7.10 (1H); 5.88 (1H); 2.66 (3H, s); 2.25 (6H, s); 1.45 (3H, s); 1.38 (3H, s); 1.32 (3H, d, J=6.8 Hz); 1.25 (3H, d, J=7.6 Hz); 1.18 (3H, d, J=6.4 Hz); 1.05 (3H, d, J=6.8 Hz); 0.93 (3H, d, J=7.2 Hz) and 0.76 (3H, t, J=7.2 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.54; 169.84; 167.07; 156.85; 133.90; 133.21; 130.84; 128.58; 125.11; 123.35; 106.83; 105.41; 103.89; 81.18; 79.60; 78.52; 77.17; 70.27; 69.37; 65.90; 59.84; 51.12; 50,52; 47.76; 40.23; 38,17; 33.64; 28.56; 28.36; 25.57; 25.01; 22,22; 21:12; 20.00; 19.04; 17,19; 15.37; 14.48; 14.28 and 10.39.

MS: m/z 826 (M+H).

Example 36

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-carbazol-9-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 7.98 (2H); 7.46 (2H); 7.38 (2H); 7.12 (2H); 2.55 (3H, s); 2.23 (6H, s); 1.44 (3H, s); 1.40 (3H, s); 1.35 (3H, d, J=7.2 Hz); 1.03 (3H, d, J=6.8 Hz); 0.94 (3H, d, J=6.8 Hz); and 0.76 (3H, t, J=7.2 Hz).

MS: m/z 851 (M+H).

Example 37

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(1H-indol-3-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 8.75 (1H, br, s); 7.98 (1H); 7.55 (1H); 7.25 (1H); 7.12 (1H); 7.05 (1H); 6.86 (1H); 6.21 (1H, no, s); 2.58 (3H, s); 2.26 (6H, s); 1.44 (3H, s); 1.39 (3H, s); 1.34 (3H, d, J=6.0 Hz); 1.01 (3H, d, J=6.4 Hz); 0.92 (3H, d, J=6.8 Hz); and 0.81 (3H, t, J=7.2 Hz).

MS: m/z 800 (M+H).

Example 38

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-furan-2-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 9.18 (1H, br, s); 7.21 (1H, s); 5.93 (1H, s); 6.42 (1H, no, s); 5.93 (1H, s); 2.68 (3H, s); 2.25 (6H, s); 1.45 (3H, s); 1.44 (3H, s); 1.32 (3H, d, J=6.4 Hz); 1.26 (3H, d, J=7.2 Hz); 1.21 (3H, d, J=6.4 Hz); 1.01 (3H, d, J=6.8 Hz); 0.93 (3H, d, J=6.8 Hz) and 0.83 (3H, t, J=7.2 Hz).

13 C NMR (100 MHz, CDCl 3 ) δ: 203.71; 169.61; 167.70; 156.74; 140.73; 110.02; 104.94; 103.94; 81.34; 79.65; 78.51; 77.11; 70.34; 69.51; 65.86; 59.55; 51.11; 50.44; 47.61; 47.50; 40.25 (2C); 38.20; 33.60; 28,16; 26,22; 25.58; 25,22; 22,19; 21:17; 20:14; 19.07; 17,13; 15.39; 14.47; 14.33 and 10.47.

MS: m/z 751 (M+H).

Example 39

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrrol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 8.51 (1H, br, s); 7.21 (1H, s); 6.64 (1H); 6.05 (1H); 2.68 (3H, s); 2.33 (6H, s); 1.45 (3H, s); 1.43 (3H, s); 1.32 (3H, d, J=6.4 Hz); 1.26 (3H, d, J=7.2 Hz); 1.23 (3H, d, J=6.0 Hz); 1.01 (3H, d, J=6.8 Hz); 0.93 (3H, d, J=7.2 Hz) and 0.84 (3H, t, J=7.2 Hz).

MS: m/z 750 (M+H).

Example 40

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrazol-1-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 10.83 (1H, br, s); 7.40 (1H); 7.28 (1H); 6.20 (1H); 6.05 (1H); 2.52 (3H, s); 2.24 (6H, s); 1.45 (3H, s); 1.43 (3H, s); 1.28 (3H, d, J=6.4 Hz); 1.24 (3H, d, J=7.6 Hz); 1.19 (3H, d, J=6.4 Hz); 1.05 (3H, d, J=6.8 Hz); 0.99 (3H, d, J=6.8 Hz) and 0.80 (3H, t, J=7.2 Hz).

MS: m/z 751 (M+H).

Example 41

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-naphthalen-1-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3

-oxoerythronolide A, 11,12-carbamate

1H NMR (400 MHz, CDCl 3 ) δ: 9.32 (1H, br, s); 8.04 (1H); 7.76 (1H); 7.61 (1H); 7.40 (2H); 7.24 (1H); 2.65 (3H, s); 2.31 (6H, s); 1.44 (3H, s); 1.42 (3H, s); 1.34 (3H, d, J=6.8 Hz); 1.25 (3H, d, J=7.6 Hz); 1.23 (3H, d, J=6.0 Hz); 1.02 (3H, d, J=6.8 Hz); 0.94 (3H, d, J=6.8 Hz) and 0.79 (3H, t, J=7.6 Hz).

MS: m/z 811 (M+H).

The following compounds can be obtained from 9-deoxo-11-deoxy-5-O-desosaminyl-11-hydrazo-9-hydroxyimino-6-O-methyl-oxoerythronolide A, 11,12-carbamate and the corresponding aldehyde, using the forward described procedures:

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-1H-imidazol-2-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(2-pyridin-3-yl-thiazol-4-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3 -oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(2-phenyl-thiazol-5-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate;

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-thiophen-2-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; and

9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(7-methoxy-quinolin-4-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate.

Claims (14)

1. Compound of formula I: [image] or its pharmaceutically acceptable salts, characterized in that X is -CR7R8 or -NR7-; or X taken together with R 2 forms -N=CR 4 R 5 ; or X and R2 taken together form a heterocyclic ring of formula XVI: [image] wherein in said ring of formula XVI, r and p are each independently an integer from 1 to 3, q is 0 or 1, and X 1 is -CH 2 -, O, S, -C(O)-, -C(S)-, - SO2-, -CH=CH-, -CH(OH)CH(OH)- or -NH-; and wherein the (CH2)r and (CH2)p portions of said ring of formula XVI are optionally substituted with 1 to 4 substituents, and the nitrogen atom where X1 is -NH- is optionally substituted with one substituent, said optional substituents being independently selected from the group consisting of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo, nitro, cyano, 5- to 10-membered heterocycle, C1-C10 alkyl, -NR7R8, C6-C10 aryl, -S(O)n(C1-C10 alkyl) where n is an integer from 0 to 2, and -SO2NR7R8; R1 is H or C1-C10 alkyl, wherein 1 to 3 carbon atoms of said alkyl are optionally replaced with a heteroatom selected from O, S, and N, and said alkyl is substituted with 1 to 3 substituents independently selected from the group consist of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo, nitro, cyano, 5- to 10-membered heterocycle, C1-C10 alkyl, -NR7R8, C6-C10 aryl , -S(O)n(C1-C10 alkyl) where n is an integer from 0 to 2 and -SO2NR7R8; R2 is (i) H, R4, -C(O)R4, -C(O)OR4 or -(CR7R8)mR3 when X is -NR7, or (ii) H, R4 or -(CR7R8)mR3 when X is -CR7R8, where in both cases, ie for (i) and (ii) m is an integer from 0 to 6, and both R7 and R8 can vary for each iteration where m is greater than 1; each R3 is independently a C6-C10 aryl or a 5- to 10-membered heterocycle, wherein said aryl and heterocycle groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo nitro, cyano, 5- to 10- membered heterocycle, C6-C10 aryl, C1-C10 alkyl, -NR7R8, -S(O)n(C1-C10 alkyl ) where n is an integer from 0 to 2, and -SO2NR7R8; and each R4 and R5 is independently selected from H and C1-C12 alkyl, wherein 1 or 2 carbon atoms of said alkyl are optionally substituted with a heteroatom selected from O, S, and N, and wherein said alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo, nitro, cyano, C1-C10 alkyl, -NR7R8, C6-C10 aryl, 5- to 10-membered heterocycle, -S(O)n(C1-C10 alkyl) where n is an integer from 0 to 2, and -SO2NR7R8; R6 is H, -C(O)R3 or C1-C18 alkanoyl, where in the alkyl part of said alkanoyl group 1 or 2 carbon atoms can optionally be replaced by a heteroatom selected from O, S and N; and each R 7 and R 8 is independently H or C 1 -C 6 alkyl. 2. A compound according to claim 1, characterized in that R6 is H. 3. A compound according to claim 1, characterized in that X is -NH-. 4. A compound according to claim 3, characterized in that R2 is H. 5. A compound according to claim 1, characterized in that R1 is H, benzyl or C1-C3 alkyl or -CH2O(CH2)2OCH3. 6. A compound according to claim 3, characterized in that R2 is -(CH2)mR3 where m and R3 are as defined in claim 1. 7. A compound according to claim 6, characterized in that R3 is a 5- to 10-membered heterocycle or C6-C10 aryl. 8. Compound according to claim 7, characterized in that R3 is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, 4-pyridin-3- yl-imidazol-1-yl and pyridin-3-yl. 9. Compound according to claim 1, characterized in that said compound is selected from the group consisting of: 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-pyridin-3-yl-imidazol-1-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3 -oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-pyridin-3-yl-imidazol-1-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3 -oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(imidazo(4,5-b)pyridin-3-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3 -oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(imidazo(4,5-b)pyridin-3-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3 -oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(7-methoxy-quinolin-4-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11 ,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(7-methoxy-quinolin-4-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11 ,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propylidene)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-9-benzoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 19-deoxo-1-deoxy-5-O-desosaminyl-11-(3-benzoimidazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 19-deoxo-1-deoxy-5-O-desosaminyl-11-(3-benzoimidazol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-indazol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-carbazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-carbazol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(5-phenyl-1H-pyrrol-2-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(5-phenyl-1H-pyrrol-2-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-imidazol-1-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-imidazol-1-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-(4-chlorophenyl)-(1,2,4)oxa-diazol-5-yl)-propyl)hydrazo-9- hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-(4-chlorophenyl)-(1,2,4)oxa-diazol-5-yl)-propyl)hydrazo-9- methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 19-deoxo-1-deoxy-5-O-desosaminyl-11-(3-(3-(4-methoxyphenyl)-(1,2,4)oxa-diazol-5-yl)-propyl)hydrazo-9- hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 19-deoxo-1-deoxy-5-O-desosaminyl-11-(3-(3-(4-methoxyphenyl)-(1,2,4)oxa-diazol-5-yl)-propyl)hydrazo-9- methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-(4-pyridin-4-yl)-(1,2,4)oxa-diazol-5-yl)-propyl) hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-(4-pyridin-4-yl)-(1,2,4)oxa-diazol-5-yl)-propyl) hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-naphthalen-1-yl-propyl)-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-naphthalen-1-yl-propyl)-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-1-yl-propyl)-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-1-yl-propyl)-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-2-yl-propyl)-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-benzotriazol-2-yl-propyl)-hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate ; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(1H-indol-3-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11, 12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(1H-indol-3-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11, 12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-4-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-4-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-3-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-3-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-2-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyridin-2-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-phenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-phenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-bis-(3-phenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-bis-(3-phenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-methoxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-methoxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-methoxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-methoxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(2-methoxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(2-methoxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-hydroxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-hydroxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-methoxyphenyl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(3-methoxyphenyl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-phenylethyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-phenylethyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(4-phenylbutyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(4-phenylbutyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-furan-2-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-furan-2-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-thiophen-2-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-thiophen-2-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrrol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrrol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrazol-1-yl-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-pyrazol-1-yl-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-pyridin-3-yl-thiazol-4-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A , 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-pyridin-3-yl-thiazol-4-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A , 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-phenyl-thiazol-5-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12 - carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(2-phenyl-thiazol-5-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12 - carbamate; eoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-1H-imidazol-2-yl)-propyl)hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-1H-imidazol-2-yl)-propyl)hydrazo-9-methoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-10-epi-11-hydrazo-9-benzoxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; 9-deoxo-11-deoxy-5-O-desosaminyl-10-epi-11-hydrazo-9-hydroxyimino-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate; and pharmaceutically acceptable salts of the aforementioned compounds. 10. A pharmaceutical preparation for the treatment of bacterial infection or protozoan infection in mammals, fish or birds, characterized in that it comprises a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier. 11. Method for treating bacterial infection or protozoan infection in mammals, fish or birds, characterized by the fact that it includes the application to said mammal, bird or fish of a therapeutically effective amount of the compound according to claim 1. 12. Process for obtaining the compound of formula I: [image] or its pharmaceutically acceptable salts, where X is -CR7R8 or -NR7-; or X taken together with R 2 forms -N=CR 4 R 5 ; or X and R2 taken together form a heterocyclic ring of formula XVI: [image] wherein in said ring of formula XVI, r and p are each independently an integer from 1 to 3, q is 0 or 1, and X 1 is -CH 2 -, O, S, -C(O)-, -C(S)-, - SO2-, -CH=CH-, -CH(OH)CH(OH)- or -NH-; and wherein the (CH2)r and (CH2)p portions of said ring of formula XVI are optionally substituted with 1 to 4 substituents, and the nitrogen atom where X1 is -NH- is optionally substituted with one substituent, said optional substituents being independently selected from the group consisting of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo, nitro, cyano, 5- to 10-membered heterocycle, C1-C10 alkyl, -NR7R8, C6-C10 aryl, -S(O)n(C1-C10 alkyl) where n is an integer from 0 to 2, and -SO2NR7R8; R1 is H or C1-C10 alkyl, wherein 1 to 3 carbon atoms of said alkyl are optionally replaced with a heteroatom selected from O, S, and N, and said alkyl is substituted with 1 to 3 substituents independently selected from the group consist of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo, nitro, cyano, 5- to 10-membered heterocycle, C1-C10 alkyl, -NR7R8, C6-C10 aryl , -S(O)n(C1-C10 alkyl) where n is an integer from 0 to 2, and -SO2NR7R8; R2 is (i) H, R4, -C(O)R4, -C(O)OR4 or -(CR7R8)mR3 when X is -NR7, or (ii) H, R4 or -(CR7R8)mR3 when X is -CR7R8, where in both cases, ie for (i) and (ii) m is an integer from 0 to 6, and both R7 and R8 can vary for each iteration where m is greater than 1; each R3 is independently a C6-C10 aryl or a 5- to 10-membered heterocycle, wherein said aryl and heterocycle groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo nitro, cyano, 5- to 10- membered heterocycle, C6-C10 aryl, C1-C10 alkyl, -NR7R8, -S(O)n(C1-C10 alkyl ) where n is an integer from 0 to 2, and -SO2NR7R8; and each R4 and R5 is independently selected from H and C1-C12 alkyl, wherein 1 or 2 carbon atoms of said alkyl are optionally substituted with a heteroatom selected from O, S, and N, and wherein said alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -C(O)O(C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halo, nitro, cyano, C1-C10 alkyl, -NR7R8, C6-C10 aryl, 5- to 10-membered heterocycle, -S(O)n(C1-C10 alkyl) where n is an integer from 0 to 2 and -SO2NR7R8; R6 is H, -C(O)R3 or C1-C18 alkanoyl, where in the alkyl part of said alkanoyl group 1 or 2 carbon atoms can optionally be replaced by a heteroatom selected from O, S and N; and each R 7 and R 8 is independently H or C 1 -C 6 alkyl; characterized in that it comprises treating the compound of formula III: [image] where X and R 2 are as defined for said compound of formula I, with a compound of formula R1ONH2•HCl or R1ONH2, where R1 is as defined for said compound of formula I, in the presence of an acid, in a polar solvent. 13. The method according to claim 12, characterized in that said solvent is methanol, ethanol or isopropyl alcohol. 14. The method according to claim 12, characterized in that said acid is Py•HCl, where Py denotes pyridine or Et3N•HCl where Et is ethyl.