MXPA01005055A

MXPA01005055A - 13-membered azalides and their use as antibiotic agents

Info

Publication number: MXPA01005055A
Application number: MXPA/A/2001/005055A
Authority: MX
Inventors: John Philip Dirlam; Peter Bertinato; Robert John Rafka; Barry James Morton; Colman Brendan Ragan; Alan Elwood Blize; Carl Bernard Ziegler
Original assignee: Pfizer Products Inc
Priority date: 1998-11-20
Filing date: 2001-05-18
Publication date: 2001-12-04

Abstract

The invention relates to a method of preparing compounds of formula (1) and to pharmaceutically acceptable salts thereof. The compounds of formula (1) are antibacterial agents that may be used to treat various bacterial and protozoa infections. The invention also relates to pharmaceutical compositions containing the compounds of formula (1) and to methods of treating bacterial protozoa infections by administering the compounds of formula (1). The invention also relates to methods of preparing the compounds of formula (1) and to intermediates useful in such preparation.

Description

AZALIDAS OF 13 MEMBERS AND THEIR USE AS ANTIBIOTIC AGENTS BACKGROUND OF THE INVENTION This invention relates to new 13-membered azalides that are useful as antibacterial and antiprotozoal agents in mammals, including humans, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the new components and to methods for the treatment of bacterial infections and protozoal infections in mammals, fish and birds, by administering the new compounds to mammals, fish and birds that require such treatment. It is known that macrolide antibiotics are useful in the treatment of a broad spectrum of bacterial and protozoal infections in mammals, fish and birds. Such antibiotics include various erythromycin A derivatives, such as azithromycin. Azithromycin is commercially available and is mentioned in U.S. Patent Nos. 4,474,768 and 4,517,359, both of which are incorporated herein by reference in their entirety. Reference is made to other macrolide antibiotics in the US patent application Serial No. 60/063676, filed on October 29, 1997 (Yong-Jin Wu), in the US patent application with No. series 60/063161, filed on October 29, 1997 (Yong-Jin Wu), in the US patent application with serial No. 60/054866, filed on August 6, 1997 (Hiroko Masamune, Yong-Jin Wu, Takushi Kaneko and Paul R. McGuirk), in the United States patent application with serial No. 60 / 049980, filed on June 11, 1997 (Brian S. Bronk, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), in international application No. PCT / IB98 / 00839, filed May 29, 1998 ( Brian S. Bronk, Cheng Hengmiao, EA Glazer, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), in the US application with serial No. 60/049348, filed on June 11, 1997 (Brian S. Bronk, Hengmiao Cheng, EA Glazer, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), in the international application No. PCT / GB97 / 01810, filed July 4, 1997 (Peter Frencis Leadlay, James Stauton , Jesús Cortés and Michael Stephen Pacey), in the international application No. PCT / GB97 / 01819, presented on June 4, 1997 (Peter Francis Leadlay, James Stauton and Jesús Cortés), in the U.S. Application Serial No. 60/070358, filed January 2, 1998 (Yong-Jin Wu), in U.S. Application No. 60/070343, filed January 2, 1998 ( Dirlam) and in the US application with serial No. 60/097075, filed on August 19, 1998 (Hengmiao Cheng, Michael A. Letavic, Carl B. Ziegler, Jason K. Dutra, Brian S. Bronk) , all of which are incorporated in this document as a reference in its entirety. Without admitting that the patents and patent applications cited above are the prior art for the present application, there still remains a need in the art for 13-membered azalide antibiotic compounds that possess potent activity against a broad range of bacteria and protozoa. In the same manner as azithromycin and other macromoidal antibiotics, the new macrolide compounds of the present invention possess potent activity against various bacterial infections and protozoal infections, as described below.

BRIEF DESCRIPTION THE INVENTION The present invention relates to compounds of formula (1) 1 or a pharmaceutically acceptable salt thereof, wherein:, acetyl, 3-N, N-dimethylamino-2- methyl-5-pyrazolyl, 3-pyrazolyl, 1 - . 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N- (3-hydroxybenzyl) -3-pyrrazolyl, 3 -oxazolyl, R is hydrogen or CrC alkyl; R3 is hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C10 alkynyl, - (CH2) m (C6-C6 o aryl), - (CH2) m (C6-C6 heterocycle) or aryl, each one, if it is other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) CιO alkyl, -C (0) C2-C10 alkenyl, -C ( O) C2-C10 alkynyl, -OC (0) alkyl CC? 0 >; -OC (O) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C alkynyl) C (O) (C1-C10 alkyl) C 2 -C 0 alkenyl or C 2 -C 0 alkynyl), -C (O) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C 1 -C 10 alkyl, C 2 - alkenyl C10 or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, Ci-C ^ alkyl, C2-C0 alkenyl or C2-C10 alkynyl), alkoxy C 1 -C 10, C 6 -C 0 aryl, 5-10 membered heterocycle, hydroxy, methoxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 pyrimidyl, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl, 4-pyridylethyl; m is an integer that varies from 0 to 4; each R 4 is hydrogen, - (CH 2) m (C 1 -C aryl) or (CH 2) m (C 6 -C 10 heterocyclic), each being, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C? -C? 0 alkyl, -C (O) C2-C? 0 alkenyl, -C (O) alkynyl C2-C? 0 > -OC (O) C 0 -C 0 alkyl, -OC (O) C 2 -C 10 alkenyl, -OC (O) C 2 -C 10 alkynyl, N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 8 alkynyl) ) C (O) (C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2 -C 0 alkynyl), -C (O) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2- alkynyl) C10) (hydrogen, C, C2 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) C6-10 alkoxy, Ce-C14 aryl, and 5-10 member heterocycle, n is an integer from 0 to 5; R6 is hydrogen or methyl; each R7 is independently hydrogen, C1-C20 alkyl, C2-C20 alkenyl. C2-C2o alkynyl, -C (O) C1-C20 alkyl, -C (O) C2-C20 alkenyl, -C (O) C2-C2o alkynyl, -C (O) N (H) alkylo CC? 0, - C (O) N (H) C2-C2o alkenyl, C (O) N (H) C2-C2o alkynyl, -SO20 (O) C? -C20 alkyl, -SO2 (O) C2-C20 alkenyl, SO2 (O) C2-C2o alkynyl or -P042 *; R8 is hydrogen or methyl: R9 is or 4"-oxocladinosyl; and R12 is C1-C10 alkyl, C2-Cto alkenino, C2-C0 alkynyl, cyano, -CH2S (O) p C1-C10 alkyl, -CH2S (O) p C2-C10 alkenyl > - CH2S (O) p C2-C10 alkynyl, wherein p is an integer ranging from 0 to 2, -CH2? (C10 alkyl), -CH2O (C2-C0 alkenyl), -CH2O (alkynyl) C2-C? 0), -CH2N (hydrogen, C1-C10 alkyl, C2-C2o alkenyl or C2-C2 alkynyl) (hydrogen, C? -C10 alkyl, C2-C10 alkenyl or C2-C? Alkynyl) , - (CH 2) m (C 6 -C 0 aryl) or - (CH 2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and where the alkyl, alkenyl moieties , alkynyl, aryl and heteroaryl of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C1-C10 alkyl, -C (O) C2-C10 alkenyl , -C (O) C 2 -C 8 alkynyl 0, -OC (0) C 1 -C 0 alkyl, -OC (O) C 2 -C 10 alkenyl, -OC (0) C 2 -C 10 alkynyl, -N (hydrogen, C 1 alkyl -C10, C2-C alkenyl or α-alkynyl C 2-C? O) C (O) (C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C (O) N (hydrogen, C-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C, C2alkyl, C2-C10alkenyl or C2-C2alkynyl), -N (hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C4alkynyl) (hydrogen, C1-C4alkyl) , C2-C alkenyl or C2-C? alkynyl), C1-C10 alkoxy, Ce-Cι aryl or 5-10 membered heterocycle, hydroxy, Ci-Cß alkyl, Ci-Cß alkoxy, Ce-Cι aryl and heteroaryl 5-10 members. 2. The present invention further relates to a compound of formula (15) or a pharmaceutically acceptable salt thereof, wherein: R1 is, acetyl, 3-N, N-dimethylamino-2- propenoyl 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1 - . 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N- (3-hydroxybenzyl) -3-pyrazolyl, 3-isoxazolyl, R2 is hydrogen or C? -C alkyl; R3 is hydrogen, C -C? Alkyl, > C 2 -C 0 alkenyl, C 2 -C 0 alkynyl, - (CH 2) m (C 6 -C 0 ary!), - (CH 2) m (C 6 -C 10 heterocycle) or aryl, each being, if different from hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C 1 -C 10 alkyl, -C (O) C 2 -C 10 alkenyl, -C (O) C 2- alkynyl C10, -OC (O) C1-C10 alkyl, -OC (O) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-alkynyl C 0) C (O) (C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), -C (O) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) ( hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 8 alkynyl), -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C 1 -C 10 alkyl, C 2 alkenyl C10 or C2-C10 alkynyl), C1-C10 alkoxy, C6-C6 aryl, 5-10 membered heterocycle, hydroxyl, methoxy, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, 2-pyridyl , 3-pyridyl, 4-pyridyl, 2-pyrimidyl or, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl and 4-pyridylethyl; m is an integer that varies from 0 to 4; each R4 is hydrogen, - (CH2) m (aryl Ce-Cio) or - (CH2) m (heterocyclic Ce-Cio), each being, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (O) C2-C10 alkenyl, -C (0) C2-C alqu alkynyl, -OC (O) C 1 -C 10 alkyl, - OC (O) C 2 -C 10 alkenyl, -OC (O) alkynyl C -C 0, - N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 0 alkynyl) C (O) (C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2 -C 10 alkynyl), -C (O) N ( hydrogen, C -C 0 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C0 alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2 alkenyl -C10 or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C0 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, C6-C6 aryl, heterocyclic 5-10 members; n is an integer from 0 to 5; Rd is hydrogen or methyl; each R7 is independently hydrogen, C1-C20 alkyl, C2-C20 alkenyl. C2-C2o alkynyl, -C (0) C1-C20 alkyl, -C (O) C2-C20 alkenyl, -C (O) C2-C2o alkynyl, -C (O) N (H) CrC alkyl, - C (O) N (H) C2-C20 alkenyl, -C (O) N (H) C2-C2o alkynyl, -SO2 (O) C1-C20 alkyl, -SO2 (O) C2-C20 alkenyl, -SO2 (O) C2-C20 alkynyl or -PO42"; R8 is hydrogen or methyl; or 4"-oxocladinosyl, R10 is an alpha-branched C2-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of which may be optionally substituted with one or more hydroxyl groups, a C5-C8 cycloalkylalkyl group in which the The alkyl group is an alpha-branched C2-C5 alkyl group, a C3-Cs cycloalkyl or Cs-Cs cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl and one or more C4 alkyl groups or halogen atoms, or a 3-6 membered heteroaryl ring, containing oxygen or sulfur, which may be saturated or wholly or partly unsaturated and which may be optionally substituted by one or more C? -C alkyl groups or halogen atoms; R 10 is phenyl which may be optionally substituted with at least one substituent selected from C 1 -C alkyl groups, C 1 -C alkylthio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; Formula as formula (a) shown below: \ Y (CH2) b (CH2) d where Y is O, S or -CH2-, each of a, b, c and d is independently an integer ranging from 0 to 2 and a + b + c + d < 5; R11 is hydrogen, or -OH; and R15 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, -CH2S (0) p C1-C10 alkyl, -CH2S (0) pC2-C10 alkenyl, -CH2S (0) ) C 2 -C 10 alkynyl, wherein p is an integer ranging from 0 to 2, -CH 2 O (C 1 -C 10 alkyl), -CH 2 O (C 2 -C 0 alkenyl), -CH 2 O (C 2 -C 10 alkynyl) ), -CH 2 N (hydrogen, C 1 -C 0 alkyl, C 2 -C 0 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), - (CH 2) m ( C6-C10 aryl) or - (CH2) (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl groups residues above are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C 1 -C 10 alkyl, -C (O) C 2 -C 10 alkenyl, -C (O) C 2 alkynyl -C10, -OC (O) C 1 -C 0 alkyl, -OC (O) C 2 -C 10 alkenyl, -OC (O) C 2 -C 10 alkynyl, -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C2- alkynyl C 0) C (O) (C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2 -C 10 alkynyl), -C (O) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 alkynyl C10) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-6 alkyl) C10, C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, C6-C10 aryl or 5-10 membered heterocycle, hydroxy, C-C6 alkyl, C? -C6 alkoxy, C6-C aryl? and 5-10 membered heteroaryl, with the exception that when R15 is H, R10 is not ethyl. The present invention also relates to compounds of formula (2) and pharmaceutically acceptable salts thereof, wherein: X is -C (O) - or -CH (OR7); and R2 and R7 are as defined above, and R9 is or 4"-oxocladinosyl, and R5 is hydrogen, C1-C10 alkyl, C2-C0 alkenyl, C2-C10 alkynyl, cyano, -CH2S (O) p C1-C10 alkyl, -CH2S (O) C2-C10 alkenyl, -CH2S (O) p C2-C10 alkynyl, wherein p is an integer ranging from 0 to 2, -CH2O (C1-C10 alkyl), -CH2O (C2-C alkenyl? 0), -CH20 (C2-C10 alkynyl), -CH2N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, (hydrogen, C1-C10 alkyl, C2-C? 0 alkenyl or alkynyl C2-C10), - (CH2) m (Ce-Cio aryl) or (CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and where the alkyl moieties , alkenyl, alkynyl, aryl and heteroaryl of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C 1 -C 10 alkyl, -C (O) alkenyl C2-C10, -C (O) C2-C10 alkynyl, -OC (O) C1-C10 alkyl, -OC (O) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, alkyl of C1-C10, C2-C10 alkenyl or C2-C alkynyl) 0) C (O) (C1-C10 alkyl), C 2 -C 0 alkenyl or C 2 -C 0 alkynyl), -C (O) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C 1 -C 10 alkyl, C2-C? or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C? o alkenyl C2-C? 0 alkynyl) (hydrogen, C1-C10 alkyl, C2-C0 alkenyl or C2-C alkynyl 0 C1-C10 alkoxy, C10-C10 aryl and 5-10 membered heterocycle, hydroxy, C6-6 alkoxy alkyl, Ce-C12 aryl and 5-10 membered heteroaryl The preferred compounds of formula (2) include those in which R7 and R8 are hydrogen and R9 is The compounds of formula CL) and of formula 12) are preferably in their isolated or purified form.

The invention also relates to a pharmaceutical composition that can be used for the treatment of a bacterial infection or of a protozoal infection in a mammal, fish or bird, comprising a therapeutically effective amount of a compound of formula (1), of formula ( 2) or of formula (15), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention also relates to a method for the treatment of a bacterial infection or a protozoal infection in a mammal, fish or bird, comprising administering to said mammal, fish or bird, a therapeutically effective amount of a compound of formula (1) , of formula (2) or of formula (15) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the compound of formula (i) is that in which R 1 _ R > 6th, R > 7 ', and. G R-J8 ° _ = hydrogen; and R9 = 4"- ((R13) (R14) NCH2) cladinosyl The term" treatment ", as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial infection or a protozoal infection, as provided in the method of the present invention As used herein, unless otherwise indicated, the terms "bacterial infection or infections" and "infection or protozoal infections" include bacterial infections and protozoal infections which appear in mammals, fish and birds, as well as disorders related to bacterial infections and protozoal infections that can be treated or prevented by the administration of antibiotics such as the compounds of the present invention Such bacterial infections and protozoal infections and disorders Related to such infections, include the following, pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis is, related to infections by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus or Peptostreptococcus spp .; pharyngitis, rheumatic fever and glomerulonephritis, related to infection by Streptococcus pyogenes, streptococci of groups C and G, Clostridium diptheriae or Actinobacillus haemolyticum; respiratory tract infections related to infections by Mycoplasma pneumoniae, Legionella pneumophila, Streotococcus pneumoniae, Haemophilus influenzae or Chlamydia pneumoniae; uncomplicated infections of the skin and white tissues, abscesses and osteomyelitis, and puerperal fever related to infection by Straphylococcus aureus, coagulase-positive staphylococci, (ie, S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, the CF groups of streptococci (streptococci from minute colonies), streptococci viridians, Corynebacterium minutissimum, Clostridium spp., Or Bartonella henselae; acute infections without complications of the urinary tract related to infection by Staphylococcus saprophyticus or Enterococcus spp .; urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum or Neiserria gonorrheae; toxin diseases related to S. aureus infection (food poisoning and Toxic shock syndrome), or streptococci of groups A, B and C; ulcers related to Helicobacter pylori infection; systemic febrile syndromes related to Borrelia recurrentis infection; Lyme disease related to Borrelia burgdorferi infection; conjunctivitis, keratitis and dacryocyst related to infection by Chlamydia trachomati Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. itifluenzae or Listeria; spp .; Disseminated disease of Mycobacterium avium complex (MAC) related to infection by Mycobactenum avium or Mycobacterium intracellulare; gastroenteritis related to infection by Campylobacter jejuní; intestinal protozoa related to infection by Cryptosporidium spp .; odontogenic infection related to viridans streptococcal infection; persistent cough related to Bordetella pertussis infection; Gas gangrene related to infection of Clostridium perfringens or Bacteroides spp .; and atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae. Bacterial infections, protozoan infections and disorders related to such infections that can be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. haem., P. multocida, Mycoplasma bovis or Bordetella spp .; enteric disease of cattle related to infection by E. coli or protozoa (ie, coccidia, cryptosporidia, etc.); Dairy cow mastitis related to Staph infection. aureus, Strep. Uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp .; Corynebacterium or enterococcus spp .; porcine respiratory disease related to infection by A. pleuro., P. multocida or Mycoplasma spp .; enteric swine disease related to infection by E. coli, Lawsonia intracellularis, Salmonella or Serpulina hyodyisinteriae; bovine interdigital dermatitis (foot-rot) related to infection by Fusobacterium spp .; cattle metritis , bovine related to E. coli infection; hairy warts of! cattle related to infection by Fusobacterium necrophorum or Bacteroides nodosus; kerato-conjunctivitis of cattle related to infection by Moraxella bovis; premature abortion in cattle related to infection by protozoa (ie, neosporium); urinary tract infection in dogs and cats related to E. coli infection; Skin and soft tissue infections in dogs and cats related to Staph infection. epidermidis, Staph. intermedius, coagulase-negative staphylococci or P. multocida; and dental and oral infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas or Prevotella. In J.P. Sanford et al., "The Sanford Guide To Antimicrobial Therapy", 26th Edition, (Antimicrobial Therapy, Inc., 1996) mentions other bacterial and protozoal infections and disorders related to such infections, which can be treated or prevented according to the procedure of the present invention. The present invention also relates to a process for preparing a compound of formula (1), particularly wherein R6, R7 and R8 are hydrogens, and R1 is trans to the methyl group at position 11 of formula. { V), or a pharmaceutically acceptable salt thereof, comprising the step of contacting the compound of formula (5) wherein R9 is as defined for formula (1); R10 is an alkyl, alkenyl, alkynyl, alkoxyalkyl or C2-C8 alkylthioalkyl, alpha-branched group, any of which may optionally be substituted with one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or Cs-Cs cycloalkenyl group, any of which may optionally be substituted with methyl or one or more hydroxyl, one or more C C alkyl groups or halogen atoms; or a 3 to 6 membered heterocyclic ring containing oxygen or sulfur, which may be saturated, or wholly or partially unsaturated and which may be optionally substituted by one or more C -C alkyl groups or halogen atoms; or R10 is phenyl which may be optionally substituted with at least one substituent selected from the group C? -C alkyl, C? -C alkylthio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R10 can have as formula the formula (a) shown below: where Y is O, S or -CH2-, each of a, b, c, and d is independently an integer ranging from 0 to 2 and a + b + c + d < 5; and R11 is hydrogen or -OH, with an acid or a base, to result in the formation of a compound of formula (1). The present invention also relates to a process for preparing a compound of the formula (1), particularly wherein R6, R7 and R8 are hydrogens, and R1 is trans to the methyl group in the 11-position of formula (1) , or a pharmaceutically acceptable salt thereof, comprising the step of heating a compound of formula (5) in the presence of a solvent, to result in the formation of a compound of formula (1).

The present invention also relates to a process for the preparation of a compound of formula (15), particularly wherein R6, R7 and R8 are hydrogens and R1 is trans to the methyl group at position 11 of formula (15), or a pharmaceutically acceptable salt thereof, comprising the step of contacting the compound of formula (5) wherein R is as defined for formula (15); R10 is an alpha, branched C2-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of them optionally being substituted with one or more hydroxyl groups; a Cs-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-Cs cycloalkyl or C5-C8 cycloalkenyl group, any of which may optionally be substituted by methyl or one or more hydroxyl, one or more C? -C4 alkyl groups or halogen atoms; or a 3-6 membered heterocyclic ring containing oxygen or sulfur, which may be saturated or wholly or partly unsaturated and which may be optionally substituted by one or more C -C alkyl groups or halogen atoms; or R 10 is phenyl which may be optionally substituted with at least one substituent selected from C 1 -C alkyl groups C 1 -C 4 alkylthio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R10 can have as formula the formula (a) shown below: where Y is O, S or -CH2-, each of a, b, c and d is independently an integer ranging from 0 to 2 and a + b + c + d < 5; and R11 is hydrogen or -OH, with an acid or a base, to result in the formation of a compound of formula (15). The present invention further relates to a process for preparing a compound of the formula (15), particularly wherein R6, R7 and R8 are hydrogens, and R1 is trans to the methyl group at the 11-position of formula (15) , or a pharmaceutically acceptable salt thereof, comprising the step of heating a compound of formula (5) in the presence of a solvent, to result in the formation of a compound of formula (15). Preferred compounds of formula (5) are those in which R 10 is ethyl, isopropyl, cyclopropyl, sec-butyl, cyclobutyl, cyclopentyl, methylthioethyl or furyl, and R 11 is hydrogen; and those in which R10 is cyclopropyl and cyclobutyl and R11 is -OH. The present invention also relates to the above compounds of formula (5) which, as indicated above, are useful in the preparation of the above compounds of formula (1) or (15), and pharmaceutically acceptable salts thereof. The term "hydroxy protecting group", as used herein, unless otherwise indicated, includes acetyl, benzoyloxycarbonyl and various hydroxyl protecting groups familiar to those skilled in the art including the groups mentioned in T.W. Greene, P.G.M. Wuts, "Protective Groups In Organic Synthesis", (J. Wiley &Sons, '991). The term "halogen", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halogen groups are fluoro, chloro and bromo. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched radicals. Such cyclic moieties include cyclopropyl, cyclobutyl and cyclopentyl. The alkyl group may include one or two double or triple bonds. It is understood that for the cyclic moieties, at least three carbon atoms must be present in said alkyl and for the alkyl group to include a double or triple carbon-carbon bond, at least two carbon atoms in the alkyl group are required.

When the alkyl moiety is defined as C1-C10 alkyl, this group includes C6-C10 bicyclic groups such as a bicyclo [3.1.1] heptylmethyl group. The term "alkoxy," as used herein, unless otherwise indicated, includes -O-alkyl groups, wherein alkyl is as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by the removal of a hydrogen, such as phenyl or naphthyl, as well as carbocyclic benzene moieties condensed such as 5,6,7,8-tetrahydronaphthyl. The term "4-10 membered heterocycle", as referred to herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms, each being selected from O, S and N , where each heterocyclic group has 4 to 10 atoms in its ring system. The non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but the aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include fused benzene ring systems and ring systems substituted with one or more oxo moieties. 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. Non-aromatic heterocyclic groups include saturated and partially unsaturated ring systems. Examples of aromatic pyridinyl heterocyclic groups are, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl and thiazolyl. Heterocyclic groups having a condensed benzene ring include chroman, benzodihydrofuran and benzoimidazolyl. Heterocyclic groups having one or more oxo moieties include phthalimide and uracil. The term "5-10 membered heteroaryl", as used herein, unless otherwise indicated, includes aromatic heterocyclic groups containing one or more heteroatoms, each being selected from O, S, and N, where each Heterocyclic group has 5 to 10 atoms in its ring system. Examples of suitable 5- to 10-membered heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, (1, 2,3) - and (1, 2,4) -triazolyl, pyrazinyl, tetrazolyl, furui, thienyl, isoxazolyl, oxazolyl , pyrrolyl and thiazolyl. The term "desosaminyl", as used herein, unless otherwise indicated, refers to the group The term "cladinosyl", as used herein, unless otherwise indicated, refers to the group The term "4" - ((R13) (R14) NCH2) cladinosyl ", as used herein, unless otherwise indicated, refers to the group The term "4" -oxocladinosyl ", as used herein, unless otherwise indicated, refers to the group The term "isolated or purified form", as used herein, unless otherwise indicated, means an isolated or purified form from a reaction mixture, for example, a reaction mixture containing a 15-membered azalide leaving which is then purified to contain at least about 95% of a compound of formula (i); a bacterial culture or broth; or a natural source, for example, a vegetable or animal source, using conventional purification techniques such as chromatography, recrystallization and others known to those skilled in the art, as well as the methods described herein. The phrase "pharmaceutically acceptable salt or salts", as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the present invention. The compounds of the present invention which are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of the present invention are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as the hydrochloride salts, Hydrobromide, hydrate, 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 salts (i.e. 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)). The compounds of the present invention that include an amino moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Preferably, the compounds of formula (1) can be used as antibacterial and antiprotozoal agents when they are in admixture with the compounds of formula (5). In such a case, the ratio between a compound of formula (1) and a compound of formula 5 ranges from about 2:98 to about 40:60. The compounds of the present invention which are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention. Certain compounds of the present invention may have asymmetric centers and, therefore, exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment which may employ or contain them. The present invention includes the compounds of the present invention and the pharmaceutically acceptable salts thereof, wherein one or more hydrogens, carbons or other atoms are replaced by their isotopes. Such compounds may be useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays.

The present invention can be more fully understood by reference to the detailed description and illustrative examples which are intended to exemplify non-limiting embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention can be prepared according to schemes 1 and 2 shown below and with the description that follows. In the following schemes, unless otherwise indicated, the substituents R1, R2, R3, R4, R5, R6, R7. R8, R9, R10, R11, R12, R13, R14, R15 are as defined above.

SCHEME 1 p-TsCi, NaHCOs, Water, acetone 7 SCHEME 1 (Continued) SCHEME 2 o ' SCHEME 2 (Continued) 11 3) (R14) NCH2) cladinosyl 12 The compounds of the present invention are prepared easily. With reference to scheme 1 above, the starting compounds of formula (6) can be obtained easily, commercially or by means of conventional organic synthesis. A preferred compound of formula (6) is erythromycin A (R10 = ethyl, R11 = -OH). The compounds of formula (6) are converted to compounds of formula (5) in which R9 = cladinosyl by known means, such as those described in U.S. Patent Nos. 4,474,768 and 4,517,350. In general, the compounds of formula (6) are treated with hydroxylamine in the presence of a base, preferably an inorganic base such as an alkali metal bicarbonate or carbonate, or an alkaline earth metal carbonate, in the presence of water and a soluble organic solvent in water, to produce the oxime compounds of formula (7). A preferred compound of formula (7) is that in which R10 = ethyl and R11 = -OH. Preferably, the inorganic base is sodium carbonate and the organic solvent soluble in water is methanol. The compounds of formula (7) are then treated with an aqueous base and a reagent which converts the hydroxyl oxime group of the compounds of formula (7) to a leaving group, and finally the iminoether compounds of formula (8) are obtained. Reagents useful in this regard include, but are not limited to, p-toluenesulfonyl halides or anhydrides, methanesulfonyl halides or anhydrides, trifluoromethanesulfonyl halides or anhydrides, p-bromobenzenesulfonyl halides or anhydrides and the like. Preferably, the reagent is p-toluenesulfonyl chloride. A preferred compound of formula (8) is that in which R10 = ethyl and R11 = -OH. The compounds of formula (8) are then reduced with a conventional hydride reducing agent, preferably sodium borohydride, to produce the compounds of formula (5) wherein R9 is cladinosyl. In a preferred embodiment, the compound of formula (5) is demethylazithromycin.

The compounds of formula (5) are converted to compounds of formula (1) by procedures described herein. Those skilled in the art will understand that the compounds of formula (5) are converted to the compounds of formula (1) wherein R 1 is trans to the methyl group at position 11 of formula (1), and is R2 = methyl; R6, R7 and R8 = hydrogen; and R9 = cladinosyl. The compounds of formula (1) wherein R 1 = methyl; R6, R and R8 = hydrogen; and R9 = cladinosyl can then be converted to other compounds of formula (i), and to the compounds of formula (2), by conventional organic synthesis and by the methods described herein. The compounds of formula (5) are converted to compounds of formula (15) by procedures described herein. Those skilled in the art will understand that the compounds of formula (5) are converted to the compounds of formula (15) wherein R 1 is trans to the methyl group at position 11 of formula (15), and is R 2 = methyl; R6, R7 and R8 = hydrogen; and R9 = cladinosyl. The compounds of formula (15) wherein R 1 = R2 = methyl, R6, R7 and R8 = hydrogen; and R9 = cladininosyl can then be converted to other compounds of formula (15), and to the compounds of formula (2), by conventional organic synthesis and by the methods described herein. Those skilled in the art will understand that in addition to the compounds of formula (6), other 14-membered macrolides susceptible to ring expansion of the Beckman type, such as, for example, erythromycin B, erythromycin C and clarithromycin, can be converted into precursors of 13-membered azalides contemplated by the present invention. When it is desired that the compounds of formula (1) are those in which R9 = 4"- ((R13) (R14) NCH2) cladinosyl, the procedures outlined in scheme 2 can be employed. For example, group 2'- The hydroxyl of the desosaminyl group of the compounds of formula (5) can be protected first with a suitable protecting group, preferably with a benzyloxycarbonyl group ("Cbz") using Cbz-CI, to produce the compounds of formula (9). at a temperature from about -78 ° C to about room temperature, preferably at about 0 ° C. A preferred compound of formula (9) is that wherein R10 = ethyl and R11 = -OH. The cladinosyl group of the compounds of formula (9) can then be oxidized using conventional oxidation conditions to produce the compounds of formula (10), which carry a 4'-oxocyaninosyl group.A preferred compound of formula (10) is that in which R10 = ethyl and R11 = -OH. Oxidation conditions can be found, for example, in the Journal of Antibiotics, 1988, pages 1029-1047. Typical reaction conditions for oxidation include: (a) oxidation of Moffatt employing N-ethyl-N '- (N, N-dimethylaminopropyl) carbodiimide and DMSO in the presence of pyridinium trifluoroacetate; or (b) Swern oxidation in which the addition of oxalyl chloride and DMSO in CH 2 Cl 2 is followed by the addition of triethylamine or, as an alternative to the addition of trifluoroacetic anhydride and DMSO in CH 2 Cl 2, is followed by the addition of triethylamine. Preferably, the oxidation is a Swern oxidation which is carried out in the presence of trifluoroacetic anhydride, at a temperature of about -78 ° C to about 0 ° C. More preferably, the Swern oxidation is performed at about -60 ° C. The caronyl group of the group 4"-oxocladinosyl of the compounds of formula (10) is then converted to an epoxide, to produce the compounds of formula (11) A preferred compound of formula (11) is that in which R 0 = ethyl and R 11 is -OH The compounds of formula (10) can be converted to the compounds of formula (11) by at least two processes In a process (Process A), the compound of formula (10) is treated with (CH 3) ) 3S (O) X2, wherein X2 is halogen, -BF4 or -PF6, preferably iodine, in the presence of a base such as potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium hydride, 1, 1, 3, 3-tetramethylguanidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, potassium ethoxide or sodium methoxide, preferably a sodium-containing base such as sodium hydride, in a solvent such as THF, an ether solvent, dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), or a mixture of two or more of the above solvents, at a temperature in the range of about 0 ° C to about 60 ° C; as an alternative, with trimethylsulfonium bromide and a strong base, such as potassium fer- t-butoxide, in the presence of CH2Cl2 / THF. In their second procedure (Process B), the compounds of formula (10) are treated with (CH3) 3SX2, wherein X2 is halogen, -BF) or -PF6, preferably -BF, in the presence of a base such as tert-butoxide potassium, sodium ethoxide, sodium tert-butoxide, sodium hydride, 1,1-3,3-tetramethylguanidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non -5-ene, potassium ethoxide, potassium hexamethyldisilazide (KHMDS) or sodium methoxide, preferably KHMDS, in a solvent such as THF, an ether solvent, DMF or DMSO, or a mixture of two or more of the above solvents, to a temperature within the range of about -78 ° C to about 60 ° C. Process B is preferably used, in which trimethylsulfonium bromide and potassium tert-butoxide are used. The protective group, preferably Cbz, of the desosaminyl group of the compounds of formula (11) is hydrogenated in the presence of H 2, Pd / C and any suitable organic solvent, preferably methyl tert-butyl ether ("MTBE"), to produce the compounds of formula (12). A preferred compound of formula (12) is that in which R10 = ethyl, and R11 = -OH. Finally, the ring of the epoxide group in the 4"position of the cladinose sugar of the compounds of formula (12) is opened using HN (R13) (R14), preferably in the presence of potassium iodide, to provide the compounds of formula ( 5), wherein R9 = 4"- ((R13) (R14) NCH2) cladinosyl. Compounds of the formula HN (R13) (R14) include primary and secondary alkyl, alkenyl and alkynyl amines, and can be readily obtained by those skilled in the art. Such a reaction is advantageously carried out at a temperature from about room temperature to about 80 ° C, preferably at a temperature from about 30 ° C to about 60 ° C. The compounds of formula (5) wherein R9 = 4"- ((R13) (R1) NCH2) cladinosyl, can be converted to the compounds of formulas (1) and (15) using the procedures described herein.

It should be noted that the conversion of the compounds of formula U) to the compounds of formula (5) in which R9 = 4"- ((R13) (R14) NCH2) cladinosyl can be carried out in one step by treating the compounds of formula (10) with HN (R13) (R14) in the presence of methanol, whereby the protective group of the desosaminyl group is removed from the compounds of formula (10) .Preferably, such reaction is carried out in the presence of potassium iodide. In order to obtain the compounds of formula (5) in which R9 = 4"-oxocladinosa, simply the protective group, preferably Cbz, which resides in the 2'-hydroxyl group of the desosaminyl group of the compounds of formula (10) is removed. Methods for removing such protecting groups can be found, for example, in Greene et al., supra Surprisingly and unexpectedly, the present inventors have discovered that the compounds of formula (5), which are 15-membered azalides, can be converted to the compounds of formula (1) and (15), which are 13 membered azalides The present inventors have discovered that the conversion of the compounds of formula (5) into the compounds of formulas (1) and (15), preferably wherein R6, R7 and R8 are hydrogen, and preferably in which R1 in trans with respect to the methyl group in the 11-position of formulas (1) and (15), can be made by contacting a compound of formula (5) with an acid or base.

Useful acids in this regard include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydriodic, hydrofluoric, sulfuric and nitric acids; and organic acids, such as formic, acetic, trifluoroacetic, methanesulfonic, trifluoromethanesulfonic, benzenesulfonic and p-toluenesulfonic acids. The inorganic acids are preferably used in the form of their aqueous solutions; more preferably, the inorganic acids are used in the form of their diluted aqueous solutions, for example, < 2 M. The organic acids can be used in the form of dilute aqueous or organic solutions, in which the organic solution comprises a solvent that sufficiently dissolves both the organic acid and the compound of formula (5). Useful bases in this regard include inorganic bases, such as sodium, lithium, potassium, magnesium or calcium hydroxides; carbonates and bicarbonates of sodium, lithium or potassium; and carbonates of magnesium and bicarbonate or calcium carbonate. Also useful are organic bases such as triethylamine, ethyldiisopropylamine, pyridine, 4-dimethylaminopyridine, collidine, lutidine and mixtures thereof. Preferably, the inorganic bases are used in the form of dilute aqueous solutions. Preferably, the inorganic bases are used in the form of dilute aqueous solutions. Preferably, the organic bases are used in the form of dilute organic solutions. Inorganic or organic bases are preferred to inorganic or organic acids.

The compounds of formula (5) may be added to the acid or to the base or vice versa. Either way, the reaction of the compounds of formula (5) with the acid or base is facilitated by heating a mixture of the compound of formula (5) and an acid or base at a temperature from about room temperature to about 100. ° C, preferably at a temperature from about room temperature to about 60 ° C and, more preferably, at a temperature from about 30 ° C to about 40 ° C. Such heating can be performed for a period of from about 20 minutes to about 48 hours, preferably over a period of about 1 hour to about 36 hours. The present invention further relates to a process for preparing a compound of formula (1) and (15), or a pharmaceutically acceptable salt thereof, comprising the step of heating a compound of formula (5) in the presence of a solvent. Such heating is achieved at a temperature from about room temperature to about 100 ° C, preferably at a temperature from about room temperature to about 60 ° C and, more preferably, at a temperature from about 30 ° C to about 40 ° C. . The heating may be carried out for a period of from about 20 minutes to about 48 hours, preferably over a period of about 1 hour to about 36 hours.

Useful solvents are those which sufficiently dissolve the compounds of formula (5) and include, but are not limited to, lower alkanols, diethyl ether, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, methylene chloride, dimethylformamide, dimethisulfoxide, N-methylpyrrolidinone and the like and mixtures thereof. However, the present inventors have discovered that, surprisingly and unexpectedly, the conversion of the compounds of formula (5) to compounds of formula (1) and (15) occurs more rapidly in a solvent system comprising a protic solvent. Useful protic solvents include, but are not limited to, lower alkanols, such as methane, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and sec-butanol; phenolic compounds such as phenol, halogenophenols, naphthols and the like; water and mixtures thereof. It should be noted that, however, the protic solvent is not a carboxylic acid. When the solvent system comprises a protic solvent, the protic solvent is present in an amount of about % to about 75% by volume, preferably in an amount of about 25% to about 60% by volume. Those skilled in the art will understand that the protic solvent will be miscible in the solvent in which the compound of formula (5) is heated, when heated to the heating temperature.

Preferably, the solvent system comprises acetonitrile. More preferably, the solvent system further comprises a lower alkanol or water. When the solvent system comprises a lower alkanol, the lower alkanoi is preferably methanol. The compounds of formulas 1 and 15 can be isolated or purified by conventional means, for example, recrystallization; chromatography using a column, a preparative plate or a CHROMATOTRON® solvent; or by other means known to those skilled in the art. When chromatography is employed to isolate or purify the compounds of formula 1 and 15, the present inventors have discovered that an eluent system comprising a hydrocarbon solvent and an organic amine provides better separation results than those obtained with other eluent systems. Useful hydrocarbon solvents in this regard include, but are not limited to, pentane, hexane or hexanes, heptane, petroleum ether, benzene, toluene, xylenes and the like. Preferably, the hydrocarbon system is hexane or hexanes. Useful organic amines include, but are not limited to, diethylamine, triethylamine, ethyldiisopropylamine, pyridine, 4-dimethylaminopyridine, collidine, lutidine, and mixtures thereof. Preferably, the organic amine is diethylamine. Advantageously, the eluent system comprising a hydrocarbon solvent and an organic amine further comprises a polar organic solvent. The present inventors have discovered that the addition of the polar organic solvent to the eluent system provides for a better separation of the compounds of formula (1) and (15) from the other compounds, with respect to the eluent system which does not comprise a polar organic solvent. Useful polar organic solvents include, but are not limited to, lower alkanols, acetonitrile, dimethylformamide, dimethisulfoxide, N-methylpyrrolidinone, 1,4-dioxane, tetrahydrofuran, diethyl ether, ethyl acetate, and the like. Preferably, the polar organic solvent is acetonitrile. More preferably, the eluent system comprises hexanes, diethylamine and acetonitrile. The proportions of hydrocarbon solvent, organic amine and optionally polar organic solvent may vary, but generally, the ratio of hydrocarbon solvent to organic amine will vary from about 10: 1 to about 1: 1; preferably from about 7: 1 to about 2: 1. When the eluent system 'further comprises a polar organic solvent, the eluent system will contain the polar organic solvent in an amount between about 1% and about 15% by volume, preferably between about 1.5% and about 10% by volume. In another embodiment of the invention, the preferred compounds of formulas (1) and (15) are those in which R1 is acetyl. Especially preferred are compounds of formula (1) wherein R 1 is acetyl, R 6, R 7 and R 8 are hydrogens and R 9 = cladinosyl ("Compound 1 B", Table 1); and wherein R1 = acetyl, R6 = methyl, R7 and R8 are hydrogens, and R9 is cladinosyl ("Compound 1 E", Table 1). In addition to being useful as antibacterial and antiprotozoal agents, the compounds of formulas (1) and (15) wherein R 1 is acetyl are useful as intermediates to obtain other compounds of formulas (1) and (15), as described below . In general, the compounds of formulas (1) and (15) in which R1 is acetyl are obtained by oxidation of the compounds of formulas (1) and (15) in which R = that can be obtained by the procedures described in this document. The oxidation reaction proceeds in the presence of lead tetraacetate, sodium periodate or any other oxidizing agent that converts 1-methyl-1,2-diols to methyl ketones. Useful reaction conditions for oxidizing a 1-methyl-1,2-diol to a methyl ketone are known to those skilled in the art. Preferably, the oxidation reaction proceeds in the presence of about 1.0 to about 1.5 equivalents of lead tetraacetate per equivalent of the compound of formulas (1) and (15), and at the temperature of about -78 ° C to room temperature, preferably at a temperature of about -10 ° C to about 10 ° C and for a period of about 10 minutes to about 6 hours.

The compounds of formulas (1) and (15) in which R1 = acetyl can be converted into the compounds of formulas (1) and (15) wherein R1 = 3- N, N-dimethylamino-2-propenoyl. Such a reaction proceeds advantageously in the presence of an excess of dimethylformamide dimethylacetal. Preferably, this reaction is carried out in the absence of additional solvent. The compounds of formulas (1) and (15) in which R 1 = 3-N, N-dimethylamino-2-propenoyl can be converted into the compounds of formulas (1) and (15) wherein R 1 = 3-pyrazolyl 1 -N-substituted, by treatment of the compounds of formula (1) in which R1 = 3-N, N-dimethylamino-2-propenoyl with about 1 to about 10 equivalents of a 1-substituted hydrazine, or an acid salt Of the same. If an acid salt of a 1-substituted hydrazine is used, then the reaction mixture containing the acid salt and the compound of formulas (1) and (15) preferably also contain a weak organic acid, alkali metal or base to buffer the reaction mixture. Preferred organic bases include diisopropylethylamine, pyridine, 4-dimethylaminopyridine, lutidine, collidine and the like, and mixtures thereof. Preferably, the organic base is diisopropylethylamine. The reaction between the compounds of formulas (1) and (15) in which R1 = 3-N, N-dimethylamino-2-propenoyl and the substituted 1-hydrazine or its acid salt, is carried out in a protic solvent, such as one of those described above, at a temperature ranging from about 50 ° C to about 115 ° C, for a period of about 1 hour to about 5 days. Preferably, the protic solvent is 2-methoxyethanol or 2-propanol. The compounds of formulas (1) and (15) in which R 1 is 3-N, N-dimethylamino-2-propenoyl, can be converted into the compounds of formulas according to the process used to obtain the compounds of formulas (1) and (15) wherein R 1 = 1-N-substituted pyrazolyl, with the exception that R 3 N (H) C (= NH) NH 3 is used instead of the 1-substituted hydrazine. The procedures to obtain R3N (H) C (= NH) NH? they are known to those skilled in the art. The compounds of formulas (1) and (15) in which R1 = 3-N, N-dimethylamino-2-propenoyl, can be converted to the compounds of formulas by reacting the compounds of formulas (1) and (15), wherein R1 = 3-N, N-dimethylamino-2-propenoyl, with (R i -NH, in an aprotic solvent, at a temperature ranging from about 50 ° C to about 110 ° C, for a period of about 1 hour to about 5 days.) Methods are known to those skilled in the art.

Useful aprotic solvents include, but are not limited to, pentane, hexanes, heptane, toluene, benzene, xylenes, petroleum ether, tetrahydrofuran, 1,4-dioxane, and the like. Preferably, the aprotic solvent is toluene. The compounds of formulas (1) and (15) in which R1 is = 3-N, N-dimethylamino-2-propenoyl can be converted into the compounds of formulas (1) and (15) wherein R1 = 3- isoxazolyl by the reaction of the compound of formula (1) and (15) wherein R1 = 3-N, N-dimethyl-2-propenoyl with from about 1 to about 10 equivalents of hydroxylamine or an acid salt thereof. The reaction used to obtain the compounds of formulas (1) and (15) wherein R 1 = 3-isoxazolyl is preferably carried out in an aprotic solvent, such as one of those described above, at room temperature or at about this temperature, for a period of about one to about five days. More preferably, the aprotic solvent is 1,4-dioxane.

The compounds of formulas (1) and (15) in which R1 = acetyl, can be converted into the compounds of formula (2) wherein X = -C (0) - by reaction of the compound of formulas (1) and (15) in which R1 = acetyl with an excess of dimethylformamide dimethylacetal, to produce the compounds of formulas (1) and (15) wherein R1 is 3-N, N-dimethylamino-2-propenoyl, described above. The compounds of formulas (1) and (15) in which R1 is 3-N, N-dimethylamino-2-propenoyl are cyclized intramolecularly to provide the compounds of formula (2) wherein X = -C (0) - . Such intramolecular cyclization is advantageously carried out at a high temperature, for example, at about 110 ° C or at a higher temperature. Accordingly, the intramolecular cyclization is carried out by heating a mixture of a high-boiling solvent and a compound of formulas (1) and (15) in which R1 is 3-N, N-dimethylamino-2-propenoyl at a temperature of about 110 ° C or higher for a period of about 6 hours to about 48 hours, preferably for about 12 hours, about 24 hours. Suitable high boiling solvents include, but are not limited to, toluene, xylenes, chlorobenzene, dimethylformamide, 2-methoxyethanol, dimethisulfoxide, and the like. Preferably, the solvent with high boiling point is 2-methoxyethanol. The compounds of formula (2) wherein X = -C (0) - are converted to the compounds of formula (2) wherein X = -CH (OH) - by treatment of the compounds of formula (2) in wherein X = -C (0) - with a hydride reducing agent such as NaBH4, LiAIH4, NaAIH4, a SELECTIDE® reducing agent or other hydride reagent known to those skilled in the art. The compounds of the present invention may have asymmetric carbon atoms and, therefore, exist in different enantiomeric and diastereomeric forms. Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (eg, alcohol), separating the diastereomers and converting (eg, hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. The use of all these isomers, including the diastereomeric mixtures and the pure enantiomers, are considered part of the present invention. The compounds of the present invention which are basic in nature, are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts have to be pharmaceutically acceptable for administration to mammals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter into the compound of free base by treatment with an alkaline reagent, and subsequently converting the last free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by contacting the basic compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium 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 salt can also be precipitated in a solution of the free base in an organic solvent, by adding an appropriate mineral or organic acid to the solution. The compounds of the present invention which are acidic in nature, are capable of forming base salts with various cations. In the case of compounds that are going to be administered mammals, fish or birds, such salts have to be pharmaceutically acceptable. When a pharmaceutically acceptable salt is required, it may be desirable to initially isolate the compound of the present invention from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter into a pharmaceutically acceptable salt in an analogous procedure to that described above with with respect to the conversion of pharmaceutically unacceptable acid addition salts into pharmaceutically acceptable salts. Examples of base salts include the alkali metal or alkaline earth metal salts and, particularly, the sodium, amine and potassium salts. All these salts are prepared by conventional techniques.

The chemical bases that are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, magnesium, various amine cations, etc. These salts can be easily prepared by contacting the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable bases with cations such as sodium, potassium, calcium, magnesium, various amine cations, etc., and then evaporating the resulting solution to dryness , preferably at reduced pressure. Alternatively, they can also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, stoichiometric amounts of the reagents are preferably employed to ensure that the reaction is complete and that the maximum yields of the desired final product are obtained. The antibacterial and antiprotozoal activity of the compounds of the present invention against bacterial and protozoan pathogens is demonstrated by the ability of the compounds to inhibit the development of defined strains of human or animal pathogens.

ASSAY I Test I, described below, employs conventional methodology and interpretation criteria and is designed to provide direction for chemical modifications that can lead to compounds that circumvent defined mechanisms of macrolide resistance. In trial I, a series of bacterial strains that include a diversity of target pathogenic species, including representative species of macrolide resistance mechanisms that have been characterized, is assembled. The use of this series allows to determine the chemical structure / activity relationship with aspect to the power, spectrum of activity and structural elements or modifications that may be necessary to circumvent the resistance mechanisms. The bacterial pathogens included in the selection series are shown in the table presented below. In many cases both the parental strain susceptible to macrolides and the macrolide-resistant strain derived therefrom are available to provide a more accurate assessment of the ability of the compounds to circumvent the resistance mechanism. Strains containing the gene with the name ermA / ermB / ermC are resistant to antibiotics macrolides, lincosamides and streptogramin B, due to certain modifications (methylation) of the 23S rRNA molecules by an Erm methylase, which usually prevents the union of the three structural classes. Two types of macrolide expulsion have been described; msrA codes for a component of an expulsion system in staphylococci that prevents the entry of macrolides and streptogramins, while mefA / E codes for a transmembrane protein that seems to expel only macrolides. Inactivation of macrolide antibiotics can occur and can be mediated by 2'-hydroxyl phosphorylation. { mph) or by cleavage of macrocyclic lactone (esterase). Strains can be characterized using conventional polymerase chain reaction (PCR) technology and / or by sequencing the resistance determinant. 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), 2562-2566 (1996). The assay is performed in microtiter trays and interpreted according to the Performarce Standards for Antimicrobial Disk Susceptibility Test-Sixth Edition; Approved Standard, published by The National Committee for Clinical Laboratory Standards (NCCLS) Guidelines; To compare the strains, the minimum inhibitory concentration (MIC) is used. The compounds are initially dissolved in dimethyl sulfoxide (DMSO) as standard solutions of 40 mg / ml.

O Trial II is used par? assay the activity against Pasteurella multocida and Essay III is used to test the activity against Pasteurella haemolytica. 5 ESSAY This test is based on the liquid dilution procedure in microliter format. A single colony of P. multocida (strain 0 59A067) is inoculated into 5 ml brain / heart infusion broth (BHI). The test compounds are prepared by solubilizing 1 mg of the compound in 125 μl of dimethylsulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The concentrations of the test compound used range from 200 μg / ml to 0.098 g / ml in serial dilutions in half. The BHI inoculated with P. multocida is diluted with uninoculated BHI broth to obtain a suspension of 104 cells per 200 μ. The suspensions of BHI cells are mixed with the respective 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 exhibiting a 100% inhibition of the development of P. multocida, as determined by comparison with a non-inoculated control.

TEST lll This assay is based on the agar dilution procedure using a Steers Replicator. Two to five colonies isolated from an agar plate in BHI broth are inoculated and incubated overnight at 37 ° C with shaking (200 rpm). The next morning, 300 μl of the fully developed P. haemolytica precuitant is inoculated into 3 ml of fresh BHI broth and the mixture is incubated at 37 ° C with shaking (200 rpm). The appropriate amounts of the test compounds are dissolved in ethanol and one serial dilution is prepared in half. Two ml of the respective serial dilution is mixed with 18 ml of molten BHI agar and solidified. When the inoculated P. haemolytica culture reaches a standard McFarland density of 0.5, approximately 5 μl of the P. haemolytica culture is inoculated onto the BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubate for 18 hours at 37 ° C. The initial concentrations of the test compound vary between 100 and 200 μg / ml. The MIC is equal to the concentration of the test compound which shows a 100% inhibition of the development of P. haemolytica, as determined by comparison with a non-inoculated control.

ASSAY IV The in vivo activity of the compounds of the present invention can be determined by conventional animal protection studies well known to those skilled in the art, usually performed in mice. Mice are distributed in cages (10 per cage) after arrival and allowed to acclimate for a minimum of 48 hours before use. The animals receive an inoculation of 0.5 ml of a bacterial suspension of 3 x 103 CFU / ml (strain 59A006 of P. multocida) intraperitoneally. Each experiment has at least 3 non-medicated control groups including one infected with an exposure dose of 0.1 X and two infected with a 1X exposure dose; a group of 10X exposure data can also be used. Generally, all mice in a given study can be exposed within a period of 30-90 minutes, especially if a repeating syringe (such as a Cornwall® syringe) is used to administer the exposure.

Thirty minutes after the exposure began, the first treatment compound is administered. It may be necessary for a second person to begin dosing the compound if all animals have not received the exposure dose at the end of the 30 minute period. The routes of administration of the doses are subcutaneous or oral. Subcutaneous doses are administered to the flaccid skin of the back of the neck, while oral doses are administered by means of a feeding needle. In both cases, a volume of 0.2 ml per mouse is used. The compounds are administered 30 minutes, 4 hours and 24 hours after the exhibition. A control compound of known efficacy administered by the same route is included in each assay. The animals are observed daily and the number of survivors in each group is recorded. The control of the P. multocida model continues for 96 hours (four days) after exposure. PD50 is a calculated dose at which the tested compound protects 50% of a group of mice from mortality due to bacterial infection that could be lethal in the absence of drug treatment. The compounds of the present invention show antibacterial activity in one of the assays described above, particularly in the IV test. The compounds of the present invention and the pharmaceutically acceptable salts thereof (hereinafter "the active compounds") can be administered orally, parenterally, topically or rectally, in the treatment of bacterial or protozoal infections. In general, these compounds are administered in the most desirable manner in doses ranging from about 0.2 mg kg of body weight and per day (mg / kg / day) and about 200 mg / kg / day in a single dose or in divided doses. (ie, from 1 to 4 doses per day) although variations will necessarily occur depending on the species, weight and condition of the subject to be treated and the particular administration route chosen. However, it is most desirable to employ a dosage level that is in the range of about 4 mg / kg / day to about 50 m / kg / day. However, variations will occur depending on the species of mammal, fish or bird to be treated and their individual response to said drug, as well as the type of pharmaceutical formulation chosen and the period of time and interval in which such administration is performed. In some cases, dosage levels lower than the lower limit of the range mentioned above may be more than adequate, while in other cases even higher doses may be used without causing any harmful side effects, provided that such larger doses are first divided into several small doses. to manage them throughout the day. The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the routes indicated previously, and such administration can be carried out in a single dose or in multiple doses. More particularly, the active compounds can be administered in a wide variety of different dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, ointments , suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be conveniently 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 99% by weight. For oral administration, can tablet be used? containing various excipients such as microcrystalline cellulose, sodium citrate, sodium carbonate, dicalcium phosphate and glycine, together with various disintegrants such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with binders granulation such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for forming tablets. Solid compositions of a similar type can also be employed as fillers in gelatin capsules; Preferred materials in this regard also include lactose or milk sugar, thus high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, emulsifying and / or suspending agents, together with diluents such as water. , ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions of an active compound of sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered (preferably at a pH above 8) if necessary and the liquid diluent should first be made isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection. The preparation of all these solutions under sterile conditions is easily accomplished by conventional pharmaceutical techniques known to those skilled in the art. In addition, it is also possible to administer the active compounds of the present invention topically and this can be done by means of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with conventional pharmaceutical practice. For administration to animals, such as cattle or domestic animals, the active compounds can be administered in the food or orally as potions.

The active compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. The active compounds can also be coupled to soluble polymers, such as targeting drug vehicles. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenyl, polyhydroxyethylaspartamide-phenol or poly (ethylene oxide) -polylysine substituted with palmitoyl residues. In addition, the active compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, poly-epsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydroxypyrans. , polycyanoacrylates and crosslinked or unsympathetic block copolymers of hydrogels. The following examples further illustrate the process and intermediates of the present invention. It should be understood that the present invention is not limited to the specific details of the examples provided below. The compounds of examples 1-12 have as formula the general formula (3) shown below, with the substituents R1 and R6 indicated in table 1, shown below. The compounds were prepared as described in Examples 1-12.

TABLE 1 EXAMPLE 1 Compound 1A. Demethylazithromycin (30 g, 41 mmol) was added to deionized water (2 I) and then acetonitrile was added to effect complete dissolution (the total volume was about 4.5 I). The resulting mixture was allowed to stir at room temperature for 2 days, at which time the HPLC indicated the presence of a new peak (approximately 22% per peak area). Acetronitrile was removed in vacuo. To the resulting residue were added potassium carbonate (30 g), followed by methylene chloride (0.3 I). The mixture was stirred and the lower organic phase was removed. The aqueous phase was reextracted with methylene chloride (2 x 0.3 I). The combined organic phases were dried over sodium sulfate and then concentrated in vacuo to yield a dry foam (30 g), which was purified on a column of silica gel filled with a suspension, using 5/1 / 0.5 (v / v) / v) hexanes-diethylamine-acetonitrile. During the separation, the solvent system was changed to a 4/1 / 0.1 mixture and, finally, to 3 / 1.5 / 0.5 hexanes-diethylamine-acetonitrile. The concentration of the appropriate subsequent elution fractions yielded compound 1A as a dry foam.

EXAMPLE 2 Compound 1B. To a solution of compound 1A (7.63 g, 10.41 mmol) in methylene chloride (100 ml) at 0 ° C was added in one portion lead acetate (IV) (5.54 g, 12.49 mmol). The resulting mixture was stirred for 30 minutes at 0 ° C and then quenched with a saturated solution of aqueous sodium bicarbonate (100 ml). The mixture was transferred to a separatory funnel and the methylene chloride layer was removed. The aqueous layer was extracted with methylene chloride (2 x 50 ml). The combined methyl chloride fractions were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 0.2% ammonium hydroxide (10% aqueous) / 5% methanol / 94.8% methylene chloride, to yield compound 1B (5.64 g, 8.43 mmol) in form a white solid.

EXAMPLE 3 Compound 1 C. Compound 1 B (100 mg, 0.15 mmol) was dissolved in dimethylformamide dimethyl acetal (2 ml) and the mixture was refluxed under nitrogen for 8 hours. The mixture was allowed to cool to room temperature and then diluted with ethyl acetate (25 ml). The mixture was washed with water (10 ml) and brine (10 ml). The ethyl acetate solution was dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 0.2% ammonium hydroxide (10% aqueous) / 10% methanol / methylene chloride to yield compound 1C (yield: 65 mg, 60%).

EXAMPLE 4 Compound 1 D. Compound 1C (100 mg, 0.14 mmol) and hydrazine monohydrate (5 mL, 0.15 mmol) were dissolved in 2-methoxyethanol (1.5 mL) and the mixture was heated to 105 ° C under nitrogen atmosphere. After 2 hours, the mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 0.2% ammonium hydroxide (10% aqueous) / 10% methanol / methylene chloride to provide compound 1 D as a white solid (yield: 58 mg, 60%).

EXAMPLE 5 Compound 1 E. To a solution of compound 1B (3.9 g, 5.8 mmol) in chloroform (58 ml) was added formic acid (330 ml, 869 mmol) and formaldehyde (37% aqueous, 1.3 ml, 17.33 mmol). The mixture was heated at 60 ° C for 7 hours. After cooling to room temperature, the mixture was transferred to a separatory funnel and washed with aqueous sodium bicarbonate (20 ml). The chloroform fraction was dried over magnesium sulfate, filtered and concentrated to provide compound 1E (yield: 3.9 g, 98%), which was used without further purification.

EXAMPLE 6 Compound 1 F. Compound 1 E was dissolved in dimethylformamide dimethylacetal (25 ml) and heated to reflux under nitrogen for 36 hours. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 0.2% ammonium hydroxide (10% aqueous) / 8% methanol / methylene chloride, to provide compound 1F (yield: 1.36 g, 80%).

EXAMPLE 7 Compound 1 G. Compound 1F (250 mg, 0.34 mmol) was dissolved in • hydrazine monohydrate (16 ml, 0.5 mmol) in 2-methoxyethanol (3.4 ml) and the mixture was heated to 105 ° C under a nitrogen atmosphere. After 4 hours, the mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 0.2% ammonium hydroxide (10% aqueous) / 10% methanol / methylene chloride to provide compound 1G as a white solid.

EXAMPLE 8 Compound 11. Compound 1F (250 mg, 0.34 mmol), benzyl hydrazine dihydrochloride (73 ml, 0.37 mmol) and diisopropylethylamine (180 μl, 1.02 mmol) were dissolved in 2-methoxyethanol (3.5 ml) and the mixture was heated to a 105 ° C under nitrogen atmosphere. After 48 hours, the mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 0.2% ammonium hydroxide (10% aqueous) / 10% methanol / methylene chloride to provide compound 11 as a white solid (yield: 137 mg, fifty%).

EXAMPLE 9 Compound U Compound 1 F (250 mg, 0.34 mmol), 3-hydroxybenzyl hydrazine dihydrochloride (142 ml, 0.68 mmol) and diisopropylethylamine (148 μl, 0.85 mmol) in 2-propanol (3.5 ml) were dissolved and the mixture was mixed. heated to reflux under a nitrogen atmosphere. After 5 hours, the mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 0.2% ammonium hydroxide (10% aqueous) / 10% methanol / methylene chloride to provide compound 1J as a white solid (yield: 147 mg, 53%).

EXAMPLE 10 Compound 1K. Compound 1 F (250 mg, 0.34 mmol), 4-fluorophenyl guanidine carbonate (240 mg, 0.68 mmol) and diisopropylethylamine (148 μl, 0.85 mmol) in 2-propanol (3.5 ml) were dissolved and the mixture was heated to a reflux in nitrogen atmosphere. After 24 hours, the mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 0.2% acetonitrile / 20% diethylamine / hexanes to provide compound 1 K as a white solid (yield: 120 mg, 42%).

EXAMPLE 11 Compound 1L. Compound 1 F (125 mg, 0.168 mmol), phenyl guanidine carbonate (84 mg, 0.252 mmol) and potassium carbonate (70 mg, 0.5 mmol) in 2-propanol (1.5 mL) were dissolved and the mixture was heated to reflux in a nitrogen atmosphere. After 48 hours, the mixture was allowed to cool to room temperature and then diluted with methylene chloride (25 ml). The mixture was then washed with water (10 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 0.2% ammonium hydroxide (10% aqueous) / 10% methanol / methylene chloride to provide compound 1 L (54 mg, 40%) as a solid white.

EXAMPLE 12 Compounds 1 H v 1M. Compound 1 F (260 mg, 0.35 mmol) and methyl hydrazine monohydrate (56 μl, 1.05 mmol) were dissolved in 2-methoxyethanol (3.5 ml) and the mixture was heated at 115 ° C under nitrogen. After 6 hours, the mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 1% acetonitrile / 20% diethylamine / hexanes to provide compound 1 H (yield: 42 mg, 17%) and compound 1 M (yield: 21 mg, 8%) in the form of white solids. The compounds of Examples 13-14 have as formula the general formula (4), shown below, with the substituents X indicated in Table 2, shown below. The compounds were prepared as described in examples 13-14.

TABLE 2 EXAMPLE 13 Compounds 2A and 1 C Compound 1 B (1.5 g, 2.23 mmol) was dissolved in dimethylformamide dimethylacetal (15 ml) and heated to 105 ° C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in 2-methoxyethanol (25 ml) and heated at 125 ° C for 16 hours. The mixture was allowed to cool to room temperature and then diluted with ethyl acetate (100 ml). The mixture was washed with water (2 x 20 ml) and brine (20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 0.2% ammonium hydroxide (10% aqueous) / 10% methanol / methylene chloride, to provide compounds 2A (yield: 221 mg, 15%) and 1C (833 mg, 54%).

EXAMPLE 14 Compound 2B. To a solution of compound 2A (150 mg, 0.21 mmol) in ethanol (2 ml) at 0 ° C was added in one portion sodium borohydride (33 mg, 0.84 mmol). The mixture was stirred at 0 ° C for 2 hours and then poured slowly into water (25 ml). The mixture was transferred to a separatory funnel and extracted with methylene chloride (3 x 20 ml). The combined methylene chloride fractions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 0.2% ammonium hydroxide (10% aqueous) / 5% methanol / methylene chloride, to provide compound 2B (yield: 103 mg, 71%) in shape of a white solid. The compounds of Examples 15-17 have as formula the general formula (14) shown below, with the substituents R1 indicated in Table 3, shown below. The compounds were prepared as described in examples 15-17. 14 10 TABLE 3 EXAMPLE 15 Compound 1 N (procedure A). To a 2 L Erlenmeyer flask was added demethylazithromycin (190.5 g, 259.2 mmol), methylene chloride (572 ml) and magnesium sulfate (38 g). The mixture was stirred for 10 minutes and then filtered into a 5 I round bottom flask. More methylene chloride (2285 ml) was added and the solution was cooled to 0-5 ° C. Then CBZ-CI (58.4 ml) was added for 10 minutes. The reaction was stirred at ~ 0 ° C for 6 hours and then at room temperature overnight. HPLC analysis indicated the presence of residual starting material, so that the reaction was re-cooled to ~ 0 ° C and more CBZ-CI (19.5 ml) was added in a single portion. The reaction was stirred for 5.5 hours at 0 ° C and then for 2.5 hours at room temperature. TLC indicated a complete reaction. The reaction was quenched with saturated aqueous sodium bicarbonate (1953 ml) and the phases were separated. The organic phase was dried over magnesium sulfate, then filtered and concentrated to yield the compound of formula (9) in which R10 = ethyl and R1 = -OH. To a 5 I round bottom flask containing the compound of formula (9) wherein R10 = ethyl and R11 = -OH (225.3 g) in methylene chloride (901 ml) and DMSO (450 ml) at -65 ° C, trifluoroacetic anhydride (82.4 ml) was added. The temperature was maintained at ~ 60 ° C throughout the entire addition, which was completed in 9 minutes. The reaction was stirred at -65 ° -70 ° C for 20 minutes. The reaction was quenched with triethylamine (145 ml) and then stirred at a temperature of -60 to -65 ° C for 20 minutes. Then, water (1127 ml) was added to the reaction mixture for 3 minutes, after which the temperature was raised to -2 ° C. The reaction mixture was stirred for 10 minutes and the phases were allowed to separate. The organic phase was washed with water (675 ml) and then saturated aqueous sodium chloride (675 ml). The organic phase was dried over magnesium sulfate, then filtered and the organic solvents were removed by distillation. MTBE was added and distilled to remove all traces of methylene chloride and DMSO. More MTBE was added to a total volume of 3380 ml. Dibenzoyl-D-tartaric acid monohydrate (87.8 g) in MTBE (1126 ml) was added to form a thick suspension. The mixture was heated to reflux and stirred overnight. After cooling to room temperature, the solids were collected in a Buchner funnel and washed with MTBE. The solids were dried in a drying oven at 40 ° C to yield 258.3 g of the dibenzoyl tartrate salt of the compound of formula (10) in which R10 = ethyl and R11 = -OH. To a 3 I round bottom flask were added methylene chloride (800 ml) and the dibezoyl tartrate salt of the compound of formula (10) in which R 0 = ethyl and R 11 -OH (188 g). Water (400 ml) and potassium carbonate (45.5 g) were added and the mixture was stirred at room temperature for 5 minutes. The organic phase was separated, then washed with water (250 ml) and dried over magnesium sulfate. The drying agent was removed by filtration and the resulting solution was evaporated under a stream of nitrogen to a final volume of 623 ml to produce a free base ketone. To a 5 L round bottom flask was added THF (623 ml) and trimethylsulfonium bromide (74.7 g). The resulting suspension was cooled to -10 ° C and potassium tert-butoxide (54.4 g) was added. The reaction mixture was stirred for 10 minutes at -10 ° C and then cooled to -70 ° C for 5 minutes. A solution of the free base ketone was added for 11 minutes, maintaining the temperature between -60 and -65 ° C. HPLC indicated that the reaction was complete after 90 minutes. The reaction was stopped at -60 ° C using a solution of ammonium chloride (315g) in water (1800 ml). The temperature was raised to -5 ° C during the interruption of the reaction. The reaction mixture was heated to 5-10 ° C and the phases were separated. The organic phase was dried over sodium sulfate, then filtered and concentrated to yield the compound of formula (11) wherein R10 = ethyl and R11 = -OH, (117.4 g) as a yellow foam. HPLC indicated a purity of 61.4% per peak area. To a solution of the compound of formula (11) wherein R 10-, ethyl and R, 11 = -OH (275 g, 312 mmol) in anhydrous methanol (2.75 I), potassium iodide (518 g, 3.12 g) was added. moles) and n-propylamine (250 ml, 3.04 moles). The mixture was stirred overnight at 45 ° C. The TLC indicated that the reaction had been completed. The reaction was concentrated on a rotary evaporator and the residue was partitioned between water (2.5 I) and methylene chloride (2.5 I). The pH of the aqueous phase was adjusted to 6.7 using 3N aqueous HCl. The extraction was repeated once more. The combined aqueous phases were combined with more methylene chloride (1.5 I) and the pH of the aqueous phase was adjusted to 8.5 using solid potassium carbonate. The phases were separated and the aqueous phase reextracted twice more with methylene chloride. The combined organic phases were dried over sodium sulfate and then filtered. The filtrate was concentrated on a rotary evaporator to produce a beige foam (230 g). The purification of the foam was performed on a column of silica gel filled with a suspension using a 19/3 (v / v) mixture of hexanes-diethylamine as the mobile phase. Thus, 125 g of the crude product yielded 72 g of the compound of formula (5), in which R9 = 4"- (propylaminomethyl) cladinosyl, R10 = ethyl and R11 = -OH, in the form of a white amorphous foam. compound of formula (5) in which R9 = 4"- (propylaminomethyl) clanidosyl, R10 = ethyl and R11 = -OH (10 g, 12.4 mmol) was dissolved in diethionitrile (0.5 I) at room temperature. Then deionized water (1 I) was added, which produced precipitation. Then more acetonitrile (0.5 I) was added to produce a homogeneous solution which was stirred at room temperature for 30 hours. The HPLC analysis indicated the formation of a new component comprising -20% of the total peak area. The organic solvent was removed in a rotary evaporator. Potassium carbonate (30 g) was added to the aqueous residue and then methylene chloride (0.3 I). The mixture was stirred and the lower organic phase was removed. Two more extractions were also performed (2 x 0.3 I). The combined organic phases were dried over sodium sulfate, then filtered and the resulting solution was concentrated until a dry foam (-10 g) was obtained. The resulting mixture of the compound of formula (5), in which R9 = 4"- (propylaminomethyl) cladionosyl, R10 = ethyl and R11 = -OH; and compound 1 N, was dissolved in a mixture of methylene chloride with a 19/3 (v / v) mixture of hexanes-diethylamine, poured into a column of silica gel filled with a suspension, and then eluted with the system 19/3. The eluent was changed to a 19/6 mixture of hexanes-diethylamine in fraction 56. Fractions 9-17 were combined and concentrated until a dry foam containing only unreacted starting material was obtained. Fractions 52-72 were combined and concentrated, and containing compound 1 N (purity 79% by HPLC).

EXAMPLE 16 Compound 1N (Method B). The compound of formula (5), in which R9 = 4"- (propylaminomethyl) cladinosyl, R10 = ethyl and R11 = -OH, was weighed in 6 vials (25 mg / vial) Solvents were added (0.5 per vial) ) as indicated below: Vial Solvent A 2-propanol B acetonitrile C acetonitrile (0.35 ml) / water (0.35) ml) D acetone E methanol F benzene All the vials were then heated to 50 ° C in an oil bath during 5 hours TLC analysis (using a 6/1 / 0.1 (v / v / v) mixture of hexanes-diethylamine-acetonitrile) indicated the presence of compound 1 N in all vials, however, the highest proportion was found in vials C and E, containing protic solvents.

EXAMPLE 17 Compound 1O. A mixture of the compound of formula (5) in which R9 = 4"(propylaminomethyl) cladinosyl, R10 = ethyl and R11 = -OH; and compound 1 N (-15%) (0.8 g, 0.1 mmol) was dissolved in ethyl acetate (30 ml), then potassium carbonate (0.14 g, 1 mmol) and ethylene carbonate (0.5 g, 5.67 mmol) were added and the mixture was heated to reflux under nitrogen overnight. using 19/3 (v / v) hexanes-diethylamine indicated the absence of the two starting materials.The reaction mixture was then filtered and the filtrate was concentrated to yield a dark oil which was purified under nitrogen atmosphere on a plate 4 mm CHROMATOTRON® (Harrison Reserch, Palo Alto, California), using a 19/3 (v / v) mixture of hexanes-diethylamine as eluent, fractions 8-13 were pooled and concentrated, NMR analysis indicated that this product corresponded to the 11, 12-cyclic carbonate of the starting material, fractions 18-39 contained a Onente less mobile that was re-purified on a 2 mm plate using a 3/1 (v / v) mixture of hexanes-diethylamine. The enriched fractions (16-23) were pooled and retested on a 1 mm plate in the above system to yield compound 10 in fraction 20 (30 mg). TLC and HPCL indicated that the material was of high purity. The present invention is not limited in scope by the specific embodiments described in the examples, which are considered illustrations of some aspects of the invention, and within the scope of this invention is any modality that is functionally equivalent. In fact, various modifications of the invention, in addition to those shown and described herein, will be apparent to those skilled in the art and are considered within the appended claims.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (1) 1 or a pharmaceutically acceptable salt thereof, wherein: R1 is, acetyl, 3-N, N-dimethylamino-2- propenoyl, 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N- (3-hydroxybenzyl) -3-pyrazolyl, 3-isoxazolyl, R2 is hydrogen or CrC alkyl; R 3 is hydrogen, C 1-6 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (C 6 -C 0 aryl), - (CH 2) m (C 6 -C 10 heterocycle) or aryl, each, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (0) C 2 -C 10 alkenyl, - C (0) C2-C10 alkynyl, -OC (0) C1-C10 alkyl, -OC (0) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, alkenyl C2-C10 or C2-C? Alkynyl, C (O) (C alquilo-alkyl, C C-C ?o alkenyl or C alqu-C? Alqu alkynyl), -C (O) N (hydrogen, C?-C10 alquilo alkyl, alkenyl C2-C10 or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen , C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), CrC 10 alkoxy, C 6 -C 0 aryl, 5-10 membered heterocycle, hydroxyl, methoxy, C 1 -C 10 alkyl, C 2 -C 8 alkenyl, C2-C10 alkynyl, 2-pyridyl, 3 -pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl, 4-pyridylethyl; m is an integer that varies from 0 to 4; each R 4 is hydrogen, - (CH 2) m (C 6 -C 10 aryl) or - (CH 2) m (C 6 -C 0 heterocycle), each being, if other than hydrogen, optionally substituted with 1 to 3 independently selected substituents between halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 10 alkyl, -C (O) C 2 -C 0 alkenyl, -C (O) C 2 -C 8 alkynyl, -OC (O) alkyl C2-C? 0, -OC (O) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) C (O) (C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -C (O) N (hydrogen, CC? or alkyl, C2-C? o alkenyl C2-C? 0 alkynyl) (hydrogen, C1-6 alkyl) C10, C2-C10 alkenyl or C2-C20 alkynyl) -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or alkynyl C2-C10), C1-C10 alkoxy, C6-C6 aryl, and 5-10 membered heterocycle; n is an integer from 0 to 5; R6 is hydrogen or methyl; each R 7 is independently hydrogen, C 1 -C 2 alkyl, C 2 -C 2 alkenyl, C 2 -C 20 alkynyl, -C (0) C 1 -C 20 alkyl, -C (0) C 2 -C 2 alkenium, -C (0) C 2- alkynyl C20, -C (0) N (H) C10 alkyl, -C (0) N (H) C2-C20 alkenyl, -C (0) N (H) C2-C20 alkynyl, -S02 (0) C1 alkyl -C20, -SO2 (O) C2-C20 alkenyl, -SO2 (O) C2-C2o alkynyl, or PO42"; R8 is hydrogen or methyl: R9 is or 4"-oxociadinosyl; and R12 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, -CH2S (0) p alkyl d-Cio, -CH2S (0) p alkenniium C2-C10, -CH2S (0) C2-C10 alkynyl, wherein p is an integer ranging from 0 to 2, -CH2O (C1-C10 alkyl), -CH20 (C2-C10 alkenyl), -CH20 (C2-C10 alkynyl) , - CH N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl) (hydrogen C1-C10 alkyl, C2-C10 alkenyl, C2-C0 alkynyl), - (CH2) m (C6 aryl -C? 0) or - (CH2) m (5-10 membered heteroaryl), wherein m is a number ranging from 0 to 4, and in which the alkyl, alkenyl, aikinyl, aryl and heteroaryl moieties of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) alkyl Ci-do, -C (0) alkenyl C2-C10, C (0) C2-C10 alkynyl, -OC (O) C? -C10 alkyl, -OC (O) C2-C? 0 alkenyl, -OC (O) C2-C? alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl) C (O) (C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 8 alkynyl), -C (0) N (hydrogen ^ C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C20 alkynyl) -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, C6-C6o aryl or 5-10 membered heterocycle, hydroxy, Ci-Cß alkyl, Ci-Cß alkoxy, Ce-Cι aryl and 5-10 membered heteroaryl.

2. - A compound of formula (15) fifteen or a pharmaceutically acceptable salt thereof, wherein: 1-metiI-N ~ 3- pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N- (3-hydroxybenzyl) -3-pyrazolyl, 3-isoxazolyl, R2 is hydrogen or CrC alkyl; R 3 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (CH) m (C 6 -C 6 aryl), - (CH 2) m (C 6 -C 0 heterocycle) or aryl, each, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethio, azido, -C (0) C 1 -C 10 alkyl, -C (O) C 2 -C 10 alkenyl, - C (0) C2-C10 alkynyl, -OC (0) C1-C10 alkyl, -OC (0) C2-C10 alkenyl, -OC (0) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, alkenyl C2-C10 or C2-C10 alkynyl) C (O) (C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C (O) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2 alkynyl -C10) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 aikinyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C? 0 alkenyl or C2-C10 alkynyl), C? -C10 alkoxy, C6-C? aryl, 5-10 membered heterocycle, hydroxy, methoxy, C1-C10 alkyl, C2-C10 alkenyl, C2- aikinyl C10, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyethyl, 3-pyridylethyl and 4-pyridylethyl; m is an integer that varies from 0 to 4; each R 4 is hydrogen, - (CH 2) m (C 6 -C 0 aryl) or - (CH 2) m (C 6 -C 10 heterocycle), each being, if other than hydrogen, optionally substituted with 1 to 3 independently selected substituents between halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C1-C10 alkyl, -C (O) C2-C10 alkenyl, -C (O) C2-C10 alkynyl, -OC (O) C1-C10 alkyl , -OC (O) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) C (O) (C1-C10 alkyl) , C 2 -C 0 alkenyl or C 2 -C 10 alkynyl), -C (0) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 0 alkynyl) (hydrogen, C 1 -C 10 alkyl, C 2 - alkenyl C10 or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C0 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1 alkoxy -C10, aryl C6-C? 0, 5-10 membered heterocycle; n is an integer from 0 to 5; R6 is hydrogen or methyl; each R7 is independently hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C2-C2 alkynyl, -C (O) C1-C20 alkyl, -C (O) C2-C2o alkenyl, -C (O) C2-C20 alkynyl , -C (0) N (H) C1-C10 alkyl, -C (0) N (H) C2-C2o alkenyl, -C (0) N (H) C2-C2o alkynyl, -S02 (0) C alkyl ^ o, -S02 (0) C2-C20 alkenyl, -S02 (0) C2-C20 alkynyl, or -P042"; R8 is hydrogen or methyl; or 4"-oxocladinosyl, R10 is a C2-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alpha-branched alkylthioalkyl group, any of which may optionally be substituted with one or more hydroxyl groups, a C-C8 cycloalkyl group, wherein the alkyl group is an alpha-branched C2-C5 alkyl group, a C3-C3 cycloalkyl or Cs-Cs cycloalkenyl group, any of which may optionally be substituted by methyl or one or more hydroxyl, one or more dC alkyl groups or halogen atoms or a 3 to 6 membered heterocyclic ring, containing oxygen or sulfur, which may be saturated or wholly or partly unsaturated and which may be optionally substituted by one or more CC alkyl groups or halogen atoms, or R10 is phenyl which may be optionally substituted with at least one substituent selected from alkyl groups CrC, alkylthio C? -C, halogen atoms, hydroxyl, trifluoromethyl and cyano groups, or R10 may have the formula ula (a) that is ours below: where Y is O, S or -CH2, each of a, b, c and d is independently an integer ranging from 0 to 2 and a + b + c + d < 5; R11 is hydrogen or -OH; and R15 is H, C? -C? alkyl, C2-C? alkenyl, C2-C? alkynyl, cyano, -CH2S (0) p C1-C10 alkyl, -CH2S (0) p C2-C10 alkenyl, -CH2S (0) p C2-C10 alkynyl, wherein p is an integer ranging from 0 to 2, -CH2O (C1-C10 alkyl), -CH2O (C2-C10 alkenyl), -CH2O (C2 alkynyl -C10), -CH2N (hydrogen, CC 0 alkyl, C 2 -C 0 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), - (CH 2) m ( aryl C6-C? 0) or - (CH2) m (5-10 membered heteroaryl), in the m is an integer number ranging from 0 to 4, and in which the alkyl, alkenyl, alkynyl, aryl residues and heteroaryl of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C 1 -C 10 alkyl, -C (O) C 2 -C 10 alkenyl, -C ( O) C2-C10 alkynyl, -OC (O) CC? 0 alkyl, -OC (O) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2- alkenyl C10 or C2-C10 alkynyl) C (O) (C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -C (O) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2 alkynyl -C10) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, C6-C6o aryl, or 5-10 membered heterocycle, hydroxy, CrC6 alkyl, Ci-Cd alkoxy, C6-C6 aryl, and 5-10 heteroaryl members, with the exception that when R15 is H, R10 is not ethyl.

3. The compound according to claim 2, further characterized in that R1 is R is CH3, R j6 °, D R7 '. and, R D8 ° are H and R9 is cladinosyl.

4. - The compound according to claim 1, further characterized in that R1 is

5. The compound according to any of claims 1, 2 or 3, further characterized in that R7 and R8 are hydrogen.

6. The compound according to claim 1, further characterized in that R9 is

7. The compound according to claim 2, further characterized in that R9 is

8. The compound according to claim 1 or 3, further characterized in that R 2 is -CH 2 N (hydrogen, C -C 0 alkyl, C 2 -C 10 alkenyl or C 2 -C 0 alkynyl) (hydrogen, C 1 -C 10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl).

9. The compound according to claim 2, further characterized in that R15 is -CH2N (hydrogen, C1-C10 alkyl, C2-C0 alkenyl or C2-C0 alkynyl) (hydrogen, C1-C10 alkyl, C2 alkenyl -C10 or C2-C10 alkynyl).

10. The compound according to any of claims 1, 2 or 3, further characterized in that R7 is H, acetyl or benzyloxycarbonyl.

11. The compound according to claim 2, which has as formula the formula (3)

12. - A compound whose formula is formula (3) selected from the group consisting of: the compound wherein R1 is acetyl and R6 is hydrogen; the compound wherein R1 is 3-N, N-dimethylamino-2-propenoyl and R6 is hydrogen; the compound wherein R 1 is 3-pyrazolyl and R 6 is hydrogen; the compound wherein R1 is acetyl and R6 is methyl; the compound wherein R1 is 3-N, N-dimethylamino-2-propenoyl and R6 is methyl; the compound wherein R 1 is 3-pyrazolyl and R 6 is methyl; the compound wherein R is 1-N-methyl-3-pyrazolyl and R6 is methyl; the compound wherein R 1 is 1-N-benzyl-3-pyrazolyl and R 6 is methyl; the compound wherein R 1 is 1-N- (3-hydroxybenzyl) -3-pyrazolyl and R 6 is methyl; the compound wherein R1 is 2- (4-fIuogogyl) -3-pyrimidinyl and R6 is methyl; and the compound wherein R1 is 1-N-methyl-5-pyrazolyl and R6 is methyl.

13. A compound of formula (14): or a pharmaceutically acceptable salt thereof; in which R is, acetyl, 3-N, N, dimethylamino-2- formula 3 / p. 104 propenoyl, 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N- (3-hydroxybenzyl) -3-pyrazolyl, -isoxalzolyl, R7 is independently hydrogen, C1-C20 alkyl, C2-C2o alkenyl, C2-C20 alkynyl, -C (0) C1-C20 alkyl. -C (0) C2-C2o alkenyl, -C (0) C2-C20 alkynyl, -C (0) N (H) CrC10 alkyl, -C (0) N (H) alkenium C2-C20), -C ( 0) N (H) C2-C20 alkynyl, -S02 (0) C1-C20 alkyl, -S02 (0) C2-C2o alkenyl, -S02 (0) C2-C2o alkynyl or -P02", and R13 and R 14 are independently hydrogen or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl.

14. - A compound of formula (14): or a pharmaceutically acceptable salt thereof; in which acetyl, 3-N, N-dimethylamino-2- 3-pyrazolium, 1-methyl-N-3- pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N- (3-hydroxybenzyl) -3-p -razolyl, 3-isoxazolyl,

R7 is independently hydrogen, C1-C20 alkyl, C2-C2o alkenyl, C2-C20 alkynyl, -C (0) C1-C20 alkyl, -C (0) C2-C2o alkenyl, -C (0) C2-C20 alkynyl, -C (0) N (H) C1-C10 alkyl, -C (0) N (H) C2-C20 alkenyl, -C (0) N (H) C2-C20 alkynyl, -S02 (0) C1- alkyl C20 -S02 (0) C2-C20 alkenyl, -SO (0) C2-C20 alkynyl or -P042", and R13 and R14 are independently hydrogen or C?-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl. The compound according to claim 13 or 14, further characterized in that R1 is

16. The compound according to claim 1 or 2 in isolated or purified form.

17. - A compound of formula (2) or a pharmaceutically acceptable salt thereof, wherein: X is -C (O) - or -CH (OR7); and R2 is hydrogen or C1-C4 alkyl; each R 7 is independently hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 2 alkynyl, -C (0) C 1 -C 20 alkyl, -C (0) C 2 -C 20 alkenyl, -C (0) C 2 alkylene -C20, -C (0) N (H) C1-C10 alkyl, -C (0) N (H) C2-C2o ainyl, -C (0) N (H) C2-C2o alkynyl, -S02 (0) C1-C20 alkyl, -SO2 (O) C2-C2o alkenyl, -SO2 (O) C2-C2o alkynyl, or -PO42"; R8 is hydrogen or methyl:

R9 is or 4"-oxacladinosyl; and R5 is hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, -CH2S (0) P C1-C10 alkyl, -CH2S (0) p C2- alkenyl C10, -CH2S (0) C2-C10 alkynyl, in which p is an integer ranging from 0 to 2, -CH2O (CC? 0 alkyl), -CH2O (C2-C10 alkenyl), -CH2O (alkynyl C2-C? 0), CH2N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C0 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), - (CH2 ) m (Ce-Cι aryl or - (CH 2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4 and in which the alkyl, alkenyl, alkynyl, aryl and heteroaryl of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (O) C 2 -C 10 alkenyl, -C (0 ) C 1 -C 10 alkyl, -OC (0) C 2 -C 0 alkenyl 0, -OC (0) C 2 -C 10 alkynyl, -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) C ( OR) (C1-C10 alkyl, C2-C10 alkenyl or C2-C20 alkynyl), -C (0) N (hydrogen, C1-C0 alkyl, C2-C10 alkenyl or Q2-C10 alkynyl) (hydrogen, C1-6alkyl) C10, C2-C? O alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-alkynyl) C10), C1-C10 alkoxy, aryl CT-CIO and 5-10 membered heterocycle, hydroxy, CrCß alkyl, C-C6 alkoxy, C6-C6 aryl and 5-10 membered heteroaryl. 18. The compound according to claim 17, further characterized in that R7 and R8 are hydrogen.

19. The compound according to claim 17, characterized further because R9 is and R 13 and R 14 are independently hydrogen or C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl.

20. - The compound according to claim 17 selected from the group consisting of: the compound wherein X is -C (O) -; and the compound wherein X is -CH (OH).

21. The compound according to claim 17, in isolated or purified form.

22. A pharmaceutical composition useful for the treatment of a bacterial infection or a protozoal infection in a mammal, fish or bird, comprising a therapeutically effective amount of a compound of claim 1 or 2 and a pharmaceutically acceptable carrier.

23. The use of a compound as claimed in claim 1 or 2 for the manufacture of a medicament for treating a bacterial infection or a protozoal infection in a mammal, fish or bird.

24. A pharmaceutical composition useful for the treatment of a bacterial infection or a protozoal infection in a mammal, fish or bird, comprising a therapeutically effective amount of a compound of claim 16 and a pharmaceutically acceptable carrier.

25. The use of a compound as claimed in claim 16 for the preparation of a medicament for treating a bacterial infection or a protozoal infection in a mammal, fish or bird.

26. - A process for preparing a compound of formula 1 in which R is trans with respect to the methyl group in the 11-position of the formula CD. acetyl, 3-N, N-dimethylamino 2-propenoyl, N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N- (3-hydroxybenzyl) -3-pyrazolyl, isoxazolyl, R2 is hydrogen, CrC4 alkyl; R3 is hydrogen, C1-C10 alkyl, C2-C10 alkeniio, C2-C10 alkynyl, - (CH2) (C6-C6 o aryl), - (CH2) m (heterocyclic or C6-C? O) or aryl, each being, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C1-C10 alkyl, -C (O) alkenyl Q2-C10, -C (O) C2-C10 alkynyl, -OC (O) alkyl CC ^, -OC (0) C2-C10 alkenyl, -OC (0) C2-C0 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C2 alkynyl) C (0) (C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -C (O) N (hydrogen, C1-C10 alkyl, C2- alkenyl C 0 or C 2 -C 10 alkynyl), -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), C 1 -C 10 alkoxy, Ce-Cι aryl, 5-10 membered heterocycle, hydroxyl, methoxy , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- pyridilethium, 3-pyridylethyl and 4-pyridylethyl; m is an integer that varies from 0 to 4; each R 4 is hydrogen, - (CH 2) m (C 1 -C aryl) or - (CH 2) m (C 6 -C 6 heterocycle), each being, if other than hydrogen, optionally substituted with 1 to 3 independently selected substituents between halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (0) C 2 -C 10 alkenyl, -C (0) C 2 -C 10 alkynyl, -OC (0) C 1 -C 10 alkyl , -OC (0) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C alkynyl), -C (O) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or Q 2 -C 10 alkynyl), -N (hydrogen, C 1 -C 10 alkyl, C 2 alkenyl -C10 or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, C6-C6 aryl and 5-10 membered heterocycle; n is an integer from 0 to 5; R6, R7 and R8 are hydrogen; R9 is or 4"-oxocladisolo, and R12 is H, C1-alkyl C10, C2-C10 alkenyl or C2-C10 alkynyl, cyano, -CH2S (0) p C1-C10 alkyl, -CH2S (0) C2-C10 alkenyl, -CH2S (0) C2-C10 alkynyl, wherein p is an integer ranging from 0 to 2, -CH2O (C1-C10 alkyl), -CH2? (C2-C alkenyl or), -CH20 (C2-C10 alkynyl), -CH2N (hydrogen, C1-C10 alkyl , C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), - (CH2) m (C6-C6 o aryl) or - (CH2) m ( 5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) CιO alkyl, -C (0) C 2 -C 0 alkenyl, -C (0) C 2 -C 10 alkynyl, -OC (0) ) alkyl CrC10, -OC (0) alkenyl C2-C0, -OC (0) alkynyl C2-C? 0) -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C alkynyl 0) C (O) (C1-C10 alkyl, C2-C10 alkenium or C2-C10 alkynyl, -C (0) N (hydrogen, O1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C2 alkynyl), C1-C10 alkoxy, C6-C aryl ? oo 5-10 membered heterocycle, hydroxy, C? -C6 alkyl, C? -C6 alkoxy, C6-C? 0 aryl and 5-10 membered heteroaryl, which comprises the step of contacting a compound of formula ( 5) wherein R9 is as defined in the compound of formula (1); R10 is an alpha, branched C2-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of which optionally being substituted with one or more hydroxyl groups; a Cs-Ce cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl, one or more C1-C4 alkyl groups or halogen atoms; or a 3 to 6 membered heterocyclic ring, containing oxygen or sulfur, which may be saturated or wholly or partially unsaturated and which may be optionally substituted by one or more C? -C alkyl groups or halogen atoms; or R 10 is phenyl which may be optionally substituted with at least one substituent selected from C 1 -C 4 alkyl groups, C 1 4 alkylthio, halogen atoms, hydroxyl groups, trifluoromethyl and cyano; or R10 can have as formula the formula (a) shown below: where Y is O, S or -CH2-, each of a, b, c and d is independently an integer ranging from 0 to 2 and a + b + c + d < 5; and R11 is hydrogen or -OH, with an acid or base to result in the formation of a compound of formula (1_).

27. A process for the preparation of a compound of formula (15) 15 or a pharmaceutically acceptable salt thereof, wherein: R 'acetyl, 3-N, N-dimethylamino-2-propenoyl, methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N- (3-hydroxybenzyl) -3-pyrazolyl, 3-isoxalyl, R 2 is hydrogen or C 1 -C 4 alkyl; R 3 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (CH 2) m (C 6 -C 0 aryl), - (CH 2) m (C 6 -C 6 heterocycle) or aryl, each, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (O) C 2 -C 10 alkenyl, -C (O) C2-C alkynyl-0, -OC (O) C1-C10 alkyl, -OC (0) C2-C10 ayenyl, -OC (0) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C2-C2 alkynyl) C (0) (C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -C (0) N (hydrogen, C1-C10 alkyl, C2 alkenyl -C10 or C2-C10 alkynyl) (hydrogen, C-C10 alkyl, C2-C10 alkenyl or C-C9 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) ( hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2 -C 10 alkynyl), C 1 -C 10 alkoxy, C 6 -C 6 aryl, 5-10 membered heterocycle, hydroxyl, methoxy, C 1 -C 10 alkyl, C 2 alkenyl -C10, C2-C10 alkynyl, 2-pyridyl, 3-p iridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl and 4-pyridylethyl; m is an integer that varies from 0 to 4; each R 4 is a hydrogen, - (CH 2) m (C 6 -C 10 aryl) or - (CH 2) m (C 6 -C 0 heterocycle), each being, other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (0) C 2 -C 10 alkenyl, -C (0) C 2 -C 0 alkynyl, -OC (O) C C10 alkyl, -OC (O) C2-C? 0 alkynyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C alkenyl) C (O) ) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, C6-C6 aryl, 5-10 membered heterocycle; n is an integer from 0 to 5; R6 is hydrogen or methyl; each R7 is independently hydrogen, C1-C20alkyl, C2-Calkynyl or C2-C2alkynyl, -C (O) C1-C20alkyl, -C (0) C2-C2 alkenyium -C (0) C2alkynyl C20 -C (0) N (H) C1-C10 alkyl, -C (0) N (H) C2-C alkenyium or, -C (0) N (H) C2-C20 alkynyl, -S02 (O) C 1 -C 20 alkyl, -S02 (O) C2-C2o alkenyl, -S02 (O) C2-C2o alkynyl or -P02"; R8 is hydrogen or methyl; R9 is or 4" -oxocladinosyl; R10 is an alpha, branched C2-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of which optionally being substituted with one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, any of which may optionally be substituted by methyl or one or more hydroxyls, one or more C1-C4 alkyl groups or halogen atoms; or a 3 to 6 membered heterocyclic ring, containing oxygen or sulfur, which may be saturated or wholly or partially unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms; or R10 is phenyl which may be optionally substituted with at least one substituent selected from C1-C4 alkyl, alkylthio Cr C, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R10 can have as formula the formula (a) shown below: where Y is O, S or -CH2-, each of a, b, c and d is independently an integer ranging from 0 to 2 and a + b + c + d < 5; R11 is hydrogen or -OH; and R15 is H, CC alkyl or, C2-C? alkenium, C2-C10 alkynyl, cyano, -CH2S (0) p C1-C10 alkyl, -CH2S (0) pC2-C10 alkenyl, -CH2S (0) C 2 -C 0 alkynyl 0, wherein p is an integer ranging from 0 to 2, -CH 20 (C 1 -C 10 alkyl), -CH 2 O (C 2 -C 10 alkenyl), -CH 2 (C 2 -C 10 alkynyl), -CH2N (hydrogen, C1-C10 alkyl, C2-C2 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), - (CH2) m (C6- aryl) C? O) or - (CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and in which the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro and trifluoromethyl, azido, -C (O) C1-C10 alkyl, -C (O) C2-C10 alkenyl, -C (O) alkynyl C2-C10, -OC (O) C 1 -C 0 alkyl, -OC (O) C 2 -C 10 alkenyl, -OC (O) C 2 -C 10 alkynyl, -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl or alkynyl C2-C10) C (O) (C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 0 alkynyl, -C (O) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 20 alkenyl or C 2 -C 10 alkynyl ) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2- alkenyl) C10 or C2-C10 alkynyl), C1-C10 alkoxy, C6-C? Ar aryl or 5-10 membered heterocycle, hydroxy, C?-C6 alkyl, Ci-Ce alkoxy, C6-C? Aryl and heteroaryl 5- 10 members, comprising the step of contacting a compound of formula (5) wherein R9, R10, and R11 are as defined above, with an acid or base, to result in the formation of the compound of formula (15).

28. A process for the preparation of a compound of formula (1) wherein R1 is trans to the methyl group at the 11-position of the formula (i), acetyl, 3-N, N-dimethylamino-2-propenoyl, -methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N- (3-hydroxybenzyl) -3-pyrazolyl, 3-izoxazolyl, R2 is hydrogen or C? -C alkyl; R 3 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (CH 2) (C 6 -C 0 aryl), - (CH) m (C 6 -C 0 heterocycle) or aryl, each one, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C 1 -C 10 alkyl, -C (O) C 2 -C 10 alkenyl, -C (O) C2-C alkynyl-0, -OC (O) C1-C10 alkyl, -OC (O) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) C (O) (C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -C (O) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C2 alkynyl), C1-6 alkoxy C10, Ce-Cιι aryl, 5-10 membered heterocycle, hydroxyl, methoxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl; 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl and 4-pyridylethyl; m is an integer that varies from 0 to 4; each R4 is hydrogen, - (CH2) m (aryl Ce-Cio) or - (CH2) m (Ce-Cio heterocycle), each being, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen , cyano, nitro, trifluoromethyl, azido, -C (O) C1-C10 alkyl, -C (O) C2-C10 alkenyl, -C (O) C2-C10 alkynyl, -OC (O) Ci-Cio alkyl, - OC (O) C2-C alkenyl 0; -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) C (O) (C -C0 alkyl, C2-C10 alkenyl or C2-C alkynyl ? 0), -C (O) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N ( hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenylene, or C2-C10 alkynyl), C1-C10 alkoxy, Ce-C14 aryl, and 5-6 heterocycle. 10 members; n is an integer from 0 to 5; R6, R7 and R8 are hydrogen; R9 is or 4"-oxocladinosyl; C1-C10, C2-C10 alkenyl, C2-C10 alkynyl, cyano, -CH2S (0) p alkyl CrC? 0, -CH2S (0) p alkenyl C2-C10, -CH2S (0) p C2-C1o alkynyl, wherein p is an integer ranging from 0 to 2, -CH20 (C1-C10 alkyl), -CH2O (C2-C10 alkenyl), -CH2O (C2-C10 alkynyl), -CH2N ( hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), - (CH 2) m (C 6 -C 6 aryl) or - (CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro and trifluoromethyl, azido, -C (O) C1-C10 alkyl, -C (O) C2-C10 alkenyl, -C (O) C2-C10 alkynyl, - OC (O) C 1 -C 10 alkyl, -OC (O) C 2 -C 0 alkenyl 0, -OC (O) C 2 -C 10 alkynyl, -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or alkynyl or C2-C10) C (O) (C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -C (O) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), (hydrogen, C? -C? 0 alkyl); C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, Ce-Cι aryl or 5-10 membered heterocycle, hydroxy, Ci-Ce alkyl, Ci-Cβ alkoxy, Ce-Cι aryl and 5-10 heteroaryl members, comprising the step of heating a compound of formula (§) wherein R9 is as defined in the compound of formula (1); R10 is an alpha-branched C2-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of which may optionally be substituted with one or more hydroxyl group; a C5-C8 cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, any of which may optionally be substituted by methyl or one or more hydroxyls, one or more C1-C4 alkyl groups or halogen atoms; or a 3 to 6 membered heterocyclic ring, containing oxygen or sulfur, which may be saturated, or wholly or partially unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms; or R10 is phenyl which may be optionally substituted with at least one substituent selected from C1-C alkyl, C1-C4 alkylthio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R10 can have as formula the formula (a) shown below: where Y is O, S or -CH2-, each of a, b, c and d is independently an integer ranging from 0 to 2 to + b + c + d = 5; and R11 is hydrogen or -OH, in the presence of a solvent system, to result in the formation of the compound of formula (1).

29. A process for the preparation of a compound of formula (15) fifteen or a pharmaceutically acceptable salt thereof, wherein: R1 is, acetyl, 3-N, N-dimethylamino-2-propenoyl, - 1-N-methyl-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N - (3-hydroxybenzyl) -pyrazolyl, 3-isoxazolyl, R 2 is hydrogen or C 1 -C 4 alkyl; R3 is hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) m (aryl Ce-Cio), - (CH2) m (heterocycle C6-C? O) or aryl, each being , if it is other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 0 alkyl, -C (0) C 2 -C 10 alkenyl, -C ( 0) C2-C10 aicynil, -OC (0) CrC10 alkyl, -OC (0) C2-C10 alkenyl, -OC (0) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2- alkenyl C10 or C2-C alkynyl o) C (0) (C1-C10 alkyl, C2-C0 alkenyl or C2-C10 alkynyl), -C (0) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or alkynyl C2-C10), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, alkenyl 02-0 ^ or C2-C10 alkynyl), C1-C10 alkoxy, Ce-Cio aryl, 5-10 membered heterocycle, hydroxyl, methoxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl 2-pyridylmethyl , 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl and 4-pyridylethyl; m is an integer that varies from 0 to 4; each R 4 is hydrogen, - (CH 2) m (C 6 -C 6 aryl) or - (CH 2) m (C 6 -C 6 heterocycle), each being, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (0) C 2 -C 0 alkenyl, -C (O) C 2 -C 10 alkynyl, -OC ( O) C 1 -C 10 alkyl, -OC (O) C 2 -C 0 alkenyl 0) -OC (0) C 2 -C 10 alkynyl, -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl 0 'or C 2 alkynyl C 0) C (O) (C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), -C (0) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) ( hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, Ce-Cio aryl, 5-10 membered heterocycle; n is an integer from 0 to 5; R5 is hydrogen or methyl; each R7 is independently hydrogen, C1-C20 alkyl, C2-C2o alkenyl, C2-C2o alkynyl, -C (O) C1-C20 alkyl, -C (0) C2-C20 alkenyl, -C (0) C2 alkynyl -C 2o, -C (0) N (H) C 1 -C 0 alkyl, -C (0) N (H) C 2 -C 2 alkenyl, -C (0) N (H) C 2 -C 2 alkynyl, -S02 (0) C1-C20 alkyl, -S02 (0) C2-C2o alkenyl, -S02 (0) C2-C2o alkynyl or -PO42"; R8 is hydrogen or methyl; R9 is: or 4"-oxocladinosyl; R10 'is an alpha-branched C2-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioaicyl group, any of which may optionally be substituted with one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group in which the alkyl group is a C2-C5 alpha-branched alkyl group, a C3-C8 cycloalkyl group or C5-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl, one or more C? -C4 alkyl groups or halogen atoms, or a 3 to 6 membered heterocyclic ring, containing oxygen or sulfur, which may be saturated, or wholly or partially unsaturated and which may be optionally substituted by one or more C -C alkyl groups or halogen atoms; R 10 is phenyl which may be optionally substituted with at least one substituent selected from C 1 -C 4 alkyl, C 4 alkylthio groups, halogen atoms, hydroxyl, trifluoromethyl and cyano groups, or R 10 may have as formula the formula (a) shown below: where Y is O, S or -CH2-, each of a, b, c and d is independently an integer ranging from 0 to 2 and a + b + c + d < 5; R11 is hydrogen or -OH; and R 15 is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, cyano, -CH 2 S (0) p C 1 -C 10 alkyl, -CH 2 S (0) p C 2 -C 10 alkenyl, -CH 2 S (0) C2-C10 alkynyl, wherein p is an integer ranging from 0 to 2, -CH20 (C -Cycloalkyl), -CH2O (C2-C3alkenyl), -CH2O (C2-C10 alkynyl ), -CH2N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), - (CH2) m (C aryl) Cio) or - (CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the above groups they are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C1-C10 alkyl, -C (0) C2-C10 alkenyl, -C (0) C2-C10 alkynyl , -OC (0) alkyl C ^ do, -OC (0) alkenyl C2-C? 0, -OC (0) alkynyl C2-C? 0, -N (hydrogen, C1-C10 alkyl, C2-C alkenyl? 0 or C2-C alkynyl) 0) C (O) (C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -C (0) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2 alkynyl -C10), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C0 alkyl, C2-C10 alkenyl or C2-C0 alkynyl), C1-C10 alkoxy or 5-10 membered heterocycle, hydroxy, alkyl CI-CT, alkoxy CrC6, aryl c6-C? o and 5-10 membered heteroaryl, which comprises the step of heating a compound of formula (5) wherein R9, R10 and R11 are as defined above, in the presence of a solvent system, to result in the formation of the compound of formula (15).

30. A process for the preparation of a compound of formula (15) 15 or a pharmaceutically acceptable salt thereof, wherein R1 is: R2 is hydrogen or C? -C alkyl; R3 is hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10-aikinyl, - (CH2) m (C6-C6o aryl), - (CH2) m (C6-C6o heterocycle) or aryl, each, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (0) C 2 -C 10 alkenyl, - C (0) C2-C10 alkynyl, -OC (0) C1-C10 alkyl, -OC (0) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, alkenyl C2-C10 or C2-C2 alkynyl) C (O) (C1-C10 alkyl, C2-C? O alkenyl or C2-C10 alkynyl), -C (0) N (hydrogen, C1-C10 alkyl, C2- alkenyl C10 or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C0 alkenyl or C2-C10 alkynyl) (hydrogen , C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), C 1 -C 10 alkoxy, C 6 -C 6 aryl, 5-10 membered heterocycle, hydroxyl, methoxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C2-C10 alkynyl, 2-pyridyl, 3-p iridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl and 4-pyridylethyl; m is an integer that varies from 0 to 4; each R 4 is hydrogen, - (CH 2) m (C 6 -C 6 aryl) or - (CH 2) m (Ce-Cι heterocycle), each being, if other than hydrogen, optionally substituted with 1 to 3 independently selected substituents between halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 0 alkyl, -C (O) C 2 -C 0 alkenyl, -C (O) alkynyl C -C 0) -OC (0) C 1 -C 0 alkyl, -OC (0) C 2 -C 0 alkynyl, -OC (0) C 2 -C 0 alkynyl, -N (hydrogen, C -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 8 alkynyl) ) C (O) (C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), -C (0) N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) (hydrogen , C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, C6-C6 aryl, 5-10 membered heterocycle; n is an integer from 0 to 5; R6 is hydrogen or methyl; each R 7 is independently hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 2 alkynyl, -C (O) C 1 -C 20 alkyl, -C (0) C 2 -C 2 alkenium, -C (0) C 2- alkynyl C2o, -C (0) N (H) C1-C10 alkyl, -C (0) N (H) C2-C20 alkenylene, -C (0) N (H) C2-C2o alkynyl, -S02 (0) alkyl C C2o, -S02 (0) C2-C2o ahenyl, -SO2 (O) C2-C20 alkynyl or -PO42"; R8 is hydrogen or methyl; R9 is: or 4"-oxocladinosyl; R10 is an alpha-branched C2-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of which may be optionally substituted with one or more hydroxyl groups; a C5-C8 cycloalkyl group in which the The alkyl group is an alpha-branched C2-C5 alkyl group, a C3-C8 cycloalkyl or Cs-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyls, one or more C1..C4 alkyl groups or halogen atoms, or a 3 to 6 membered heterocyclic ring, containing oxygen or sulfur, which may be saturated, or wholly or partly unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms, or R10 is phenyl which may be optionally substituted by at least one substituent selected from C1-C4 alkyl groups, C1-C4 alkylthio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups, or R10 may have the formula Formula (a) shown below: where Y is O, S or -CH2-, each of a, b, c and d is independently an integer ranging from 0 to 2 and a + b + c + d < 5, R11 is hydrogen or -OH; and R15 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, -CH2S (O) C? -C10 palquil, -CH2S (0) C2-C10 palkenyl, -CH2S (0) palquiniio C2 -C10, where p is an integer ranging from 0 to 2, -CH20 (Cr C10 alkyl), -CH20 (C2-C10 alkenyl), -CH20 (C2-C10 alkynyl), -CH2N (hydrogen, alkyl) C1-C10, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C ^ Cio alkyl), C2-C10 alkenyl or C2-C10 alkynyl), - (CH2) m (C6-C6o aryl) or - ( CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (0) C 2 -C 10 alkenyl, -C (0) C 2 -C 10 alkynyl, -OC ( 0) C 1 -C 10 alkyl, OC (0) C 2 -C 10 alkenyl, OC (0) C 2 -C 10 alkynyl, -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 8 alkynyl) C (0) ) (C1- alkyl) C10, C2-C10 alkenyl or C2-C10 alkynyl), -C (0) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C? alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1-6 alkoxy C10, aryl C6-C? Oo 5-10 membered heterocycle, hydroxy, C? -C6 alkyl, Ci-C? Alkoxy, Ce-C y aryl and 5-10 membered heteroaryl, comprising the step of contacting a compound of formula (5) wherein R9, R10 and R11 are as defined above, with an acid or base, to result in the formation of the compound of formula (15).

31. - A method of preparing a compound of formula (15) 15 or a pharmaceutically acceptable salt thereof, wherein: R1 is: R 2 is hydrogen or C 1 -C 4 alkyl; R3 is hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) m (C6-C6o aryl), - (CH2) m (C6-C heterocycle) or aryl, each one, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) C 1 -C 10 alkyl, -C (O) C 2 -C 10 alkenyl, -C (0) C2-C10 alkylene, -OC (0) CC? 0 alkyl, -OC (0) C2-C10 alkenyl, -OC (0) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C 2 -C 0 alkenyl or C 2 -C 0 alkynyl) C (O) (C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), -C (0) N (hydrogen, C 1 -C 10 alkyl, C 2 alkenyl -C10 or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, C6-C0 aryl, 5-10 membered heterocycle, hydroxy, methoxy, C1-C10 alkyl, C2-C10 alkenyl, C2 alkynyl -C10, 2-pyridyl, 3-p iridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylethyl and 4-pyridylethyl; m is an integer that varies from 0 to 4; each R4 is hydrogen, - (CH2) m (aryl Ce-C o) or - (CH2) m (C6-C10 heterocycle), each being, if other than hydrogen, optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C 1 -C 10 alkyl, -C (0) C 2 -C 10 alkenyl, -C (0) C 2 -C 10 alkynyl, -OC (O) C 1 -C 10 alkyl, -OC (O) C2-C10 alkenyl, -OC (O) C2-C10 alkynyl, -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C alkynyl) C (O) (C1-6 alkyl) C10, C2-C10 alkenyl or C2-C10 alkynyl), -C (O) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, C6-C6 aryl, 5-10 membered heterocycle; n is an integer from 0 to 5; R6 is hydrogen or methyl; each R7 is independently hydrogen, C1-C20 alkyl, C2-C2o alkenyl, C2-C20 alkynyl, -C (O) C1-C20 alkyl, -C (0) C2-C20 alkenyl, -C (0) C2-C2 alkynyl , -C (0) N (H) C 1 -C 0 alkyl, -C (0) N (H) C 2 -C 2 alkenium, -C (0) N (H) C 2 -C 2 alkyl, -S 0 2 (0) C alkyl C2o, - S02 (0) C2-C2o alkenyl, -S0 (0) C2-C20 alkynyl or -P042-.; R is hydrogen or methyl; R9 is or 4"-oxocladinosyl; R10 is an alpha-branched C2-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of which may optionally be substituted with one or more hydroxyl groups; a Cs-C8 cycloalkylalkyl group wherein the alkyl group is a C2-C5 alpha-branched alkyl group, a C3-C8 cycloalkyl group or C5-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyls, one or more C1-C4 alkyl groups or atoms halogen, or a 3 to 6 membered heterocyclic ring, containing oxygen or sulfur, which may be saturated, or wholly or partly unsaturated and which may optionally be substituted by one or more C1-C4 alkyl groups or halogen atoms, or R10 is phenyl which may be optionally substituted with at least one substituent selected from C1-C4 alkyl groups, C1-C alkylthio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups, or R10 may have as formula the formula (a) shown below: where Y is O, S or -CH2-, each of a, b, c and d is independently an integer ranging from 0 to 2 and a + b + c + d < 5; R11 is hydrogen or -OH; and R15 is H, C-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, -CH2S (O) palquiio CC? 0, -CH2S (O) C2-C? -carkenyl 0, -CH2S (O) p C2-C10 alkynyl, wherein p is an integer ranging from 0 to 2, -CH2? (Cr C10 alkyl), -CH20 (C2-C10 alkenyium), -CH20 (C2-C10 alkynyl), -CH2N ( hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl) (hydrogen, C 1 -C 0 alkyl, C 2 -C 10 alkenyl or C 2 -C 10 alkynyl), - (CH 2) m (C 6 -C 6 aryl) or - (CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the alkyl, alkeniio, alkynyl, aryl and heteroaryl moieties of the above groups are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) C1-C10 aicyl, -C (0) C2-C10 alkenyl, -C (0) C2-C alkynyl? 0, -OC (O) C 1 -C 10 alkyl, -OC (O) C 2 -C 0 alkenyl 0) -OC (O) C 2 -C 0 alkynyl 0, -N (hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C2-C alkynyl 0) C (O) (C1- alkyl) C10, C2-C10 alkenyl or C2-C10 alkynyl), -C (O) N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 aikinyl), -N (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl) (hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl), C1-C10 alkoxy, aryl C6-C? oo 5-10 membered heterocycle, hydroxy, C? -C6 alkyl, CrC6 alkoxy, CQ-CW aryl and 5-10 membered heteroaryl, which comprises the step of heating a compound of formula (5) wherein R9, R10 and R11 are as defined above; in the presence of a solvent system, to result in the formation of the compound of formula (15).

32. The process according to any of claims 28, 29 or 31, further characterized in that the solvent system comprises a solvent selected from the group consisting of lower alkanols, diethyl ether, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, benzene , toluene, chloroform, methylene chloride, dimethylformamide, dimethisulfoxide, N-methylpyrrolidinone and mixtures thereof.

33. The process according to claims 28, 29 or 31, further characterized in that the solvent system further comprises a protic solvent.

34. The process according to claim 33, further characterized in that the protic solvent is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, phenol , halogenophenols, naphthols, water and mixtures thereof.