Field of Invention
The present invention provides ketolide derivatives, which can be used as antibacterial agents Compounds described herein can be used for treating or preventing conditions caused by or contributed to by gram positive, gram negative or anaerobic bacteria, more particularly against, for example, Staphylococci Streptococci Enterococci Haemophilus Moraxalla spp Chlamydia spp Mycoplasm Legionella spp Mycobacterium Helicobacter Clostridium Bacteroides Corynebactenum Bacillus Enterobactericeae Propionibactenum acnes or any combination thereof Also provided are processes for preparation of compounds described herein, pharmaceutical compositions thereof and methods of treating bacterial infections
Background of the Invention
First generation macrohdes erythromycin A and early derivatives are characterized by bacteriostatic or bactericidal activity for most gram-positive bacteria, atypical pathogens, and many community-acquired respiratory infections and in patients with penicillin allergy However, erythromycin A causes numerous drug-drug interactions, has relatively poor absorption, poor local tolerance, loses its antibacterial activity under acidic conditions by degradation and the degraded products are known to be responsible for undesired side effects (Itoh, Zet al ,Am J Physiol, 1984, 247 688, Omura, S et al, J Med Chem , 1987, 30 1943) Various erythromycin A derivatives have been prepared to overcome the acid instability and other problems associated with it
Roxithromycin, clarithromycin and azithromycin were developed to address the limitation of erythromycin A Both clarithromycin and azithromycin were found to be important drugs in the treatment and prophylaxis of atypical mycobacterial infections in patients with HIV
Macrohdes were found to be effective drugs in the treatment of many respiratory tract infections However, increasing resistance among S pneumoniae has prompted the search for new compounds that retain favorable safety profiles, retain a spectrum of activity and are confined to respiratory pathogens Consequently, numerous investigators have prepared chemical derivatives of erythromycin A in an attempt to obtain analogs having modified or improved profiles of antibiotic activity Ketolides exhibit greater efficacy and safety, have broader spectrum of activities, and are particularly effective against resistant pathogens, hence, ketolides have been developed as next generation macrohdes
U S Patent No 5,635,485 discloses erythromycin compounds that are reportedly useful in the treatment of bacterial infections in warm-blooded animals
U S Patent No 5,866,549 discloses novel semi-synthetic macrohdes reportedly having antibacterial activity, as well as 6-O-substituted erythromycin ketolide derivatives and a method of treating bacterial infections
US Patent Nos 6,458,771 and 6,399,582 and PCT Publication Nos WO 00/62783 and WO 00/44761 disclose ketolide antibactenals that are reportedly useful in treating bacterial and protozoal infections and in treating other conditions involving gastric motility
U S Patent No 5,747,467 discloses erythromycin and novel antibacterial composition and a method of treating bacterial infection in warm-blooded animals
US Patent No 6,433,151 discloses erythromycin derivatives and their use as medicament for treating infections caused by particular gram-positive bacteria, namely
Haemophilus influenzae and Morraxalla spp
U S Patent No 6,472,372 discloses 6-O-carbamoyl ketolide antibactenals and methods of treating bacterial infections
U S Patent Application Nos 2002/0115621 and 2003/0013665 disclose macrohde compounds that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well in fish and birds
Other ketolide compounds have also been reported A Denis and A Bonnefoy, Drugs of the Future, 26(10) 975-84 (2001), Champney W S,etal, Current Microbiology, 42 203-10 (2001)
However, there remains a need for novel ketolide derivatives, which can be used as antibacterial agents on a wide variety of gram positive, gram negative or anaerobic bacteria
Summary of the Invention
The present invention provides ketolide derivatives, which can be used in the treatment or prevention of bacterial infection, and processes for the synthesis of these compounds
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs of these compounds having same type of activity are also provided
Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of bacterial infection
Thus in one aspect, provided herein are compounds having the structure of Formula I,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof, wherein
R1 can be hydrogen or a hydroxyl protecting group,
R2 can be C2-C6 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or COR4,
R can be hydrogen, alkyl or aralkyl,
W can be (CH2)q, CR5R6, NR5 or SO2,
q can be an integer of from 2 to 10,
R5 and R6 can be independently hydrogen or alkyl,
(CH2)q group can be optionally interrupted by one or more of unsaturated bonds, oxygen, sulfur, CO, CS, SO2, NR) or combination thereof,
one or more hydrogen atoms of (CH2)q group can be optionally replaced by halogen, alkyl, hydroxyl or alkoxy,
Ri can be hydrogen, alkyl, alkenyl, alkynyl, COR2 or (CH2)mR2, R2 can be alkyl, alkenyl, alkynyl, aryl, heterocycle, R can be R6NCOR7, aryl or heterocycle,
R6 and R7 can be independently aryl or heterocycle, R can be alkyl, alkenyl or alkynyl,
R' can be alkyl or -(CH2)r-U,
r can be an integer of from 1 to 4,
U can be alkenyl or alkynyl, Z can be oxygen, sulfur or NOR ,
R4 is the same as defined earlier
These compounds can include one or more of the following features For example, R1 tan be hydrogen, R2 and R3 can be ethyl, W can be (CH2)q , wherein (CH2)q is the same as defined earlier, R' can be methyl, Z can be oxygen, and R can be heterocycle In another feature, R1 can be hydrogen, R2 and R3 can be ethyl, W can be (CH2)q, wherein (CH2)q is the same as defined earlier, R' can be methyl, Z can be oxygen, and R can be R6NCOR7,
(Formula Removed)
X1-X3 can be independently CH or N,
X4-X8 can be independently CH, CR3 or N,
X9 can be O, S, N, NH or CH,
X10 can be NH or S,
Ra can be optionally substituted thienyl, furyl, pyrazolyl, oxazolyl, tetrazolyl, lmidazolyl, pyndinyl, fluoropyndinyl, chloropyndinyl, pyridinyl, pyrazinyl, pynmidinyl, pynmidinyl, quinolinyl, pyrrolo-pyndyl, pyrrolo-thiazolyl or phenyl wherein optional substituent(s) can be methyl, halogen, methoxy, NR4R5 [wherein, R4 and R5 can be independently hydrogen, methyl, isopropyl, cyclopropyl, acetyl],
R'a can be hydrogen or furyl,
Rb can be hydrogen or NR4R5 [wherein, R4 and R5 can be independently hydrogen, methyl, isopropyl, cyclopropyl, acetyl],
Rc can be hydrogen, optionally substituted thienyl, furyl, pyrazolyl, pyrazinyl, pyndinyl, pyndinyl, pynmidinyl, pyrrolyl, lmidazolyl or phenyl wherein optional substituent(s) can be methyl, halogen, methoxy, NR4R5 [wherein, R4 and R5 can be independently hydrogen, methyl, isopropyl, cyclopropyl, acetyl],
Rd can be thienyl, pyrazolyl, lmidazolyl, tnazolyl, pyrrolyl or tetrahydrofuryl,
Re can be (heterocyclyl)alkyl,
R6 and R7 can be independently aryl or heterocyclyl
In another aspect, provided herein are compounds selected from
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(2-pyndin-3-yl-methyl-benzimidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3"-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-pyndin-3-yl-imidazol-1 -y l)-buty l)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(imidazo[4,5-b]pyndin-l-yl)-butyl)-imino)] erythromycin A, 10856
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3,4-dihydro-2H-quinohn-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyI-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,1 l-[oxycarbonyl-((4-(4-tetrazol-l-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-furan-3-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-thiophen-2-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-furan-2-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-pyrazin-2-yl-thiazol-2-yl)-butyl)-imino)] erythromycin
A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-pyndin-3-yl-thiazol-2-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-l 2,11 -[oxycarbonyl-((4-(6-pyrazol-1 -yl-pyndin-3-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(6-imidazol-1 -yl-pyndin-3-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-(3-amino phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(6-pyrrol-1 -y l)-pyndin-3-yl)-imidazol-1 -yl)-buty 1)-lmino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(6-pyrrol-1 -yl-pyndin-3-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-((4-(2-pyrrol-l-yl-thiazol-5-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-([l,4']-bnmidazol-r-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-thiaophen-2-yl-pyndin-3-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladmosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-(4-methyl-3-aminophenyl)-imidazol-l-yl)-butyl)-lmino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-(N,N-dicyclopropyl-amino)-phenyl)-imidazol-1 -yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-(3-(N,N-dimethyl-amino)-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11^12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-nicotinamido)-butyl)-imino)] erythromycin A ,

5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(2-pyrrol-1 -yl-thiazol-5-y l)-imidazol-1 -y l)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-benzamido)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-(3-(N-acetyl-amino)-phenyl)-imidazol-1 -y l)-butyl)-lmino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(3-(N-isopropyl-amino)-pheny l)-imidazol-1 -y l)-buty 1)-lmino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(4-fluoro-phenyl)-imidazol-1 -yl)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(4-methoxy-phenyl)-imidazol-l -yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(benzthiazol-2-yl)-benzamido)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-isonicotinamido)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(5-methyl-pyndin-2-yl)-benzamido)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(2-amino-pynmidin)-5-yl)-imidazol-1 -yl l)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(2-amino-pyndin)-5-yl)-imidazol-l-yl l)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(2-amino-pyndin)-4-yl)-imidazol-l-yl l)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-(4-(4-(2-amino-pynmidin)-5-yl)-pyrazol-l-yl l)-butyl)-lmino)] erythromycin A ,
or pharmaceutical^ acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof
In yet another aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds of compounds described herein together with one or more pharmaceutically acceptable carriers, excipients, or diluents
In another aspect, provided herein are methods for treating or preventing conditions caused by or contributed to by bacterial infections comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds of compounds described herein
The methods may include one or more of the following embodiments For example, the condition can be selected from community acquired pneumonia, upper or lower respiratory tract infections, skin or soft tissue infections, acne vulgaris, hospital acquired lung infections, hospital acquired bone or joint infections, mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease In another embodiment, the bacterial infection can be caused by gram positive, gram negative or anaerobic bacteria
In yet another embodiment, the gram positive, gram negative or anaerobic bacteria can be selected from Staphylococci Streptococci Enterococci Haemophilus Moraxalla spp Chlamydia spp Mycoplasm Legionella spp Mycobacterium Helicobacter Clostridium Bacteroides Corynebacterium Bacillus, Propionibacterium acnes or Enterobactericeae In a preferred embodiment, the bacterium is cocci In another preferred embodiment, the cocci is drug resistant
In another aspect provided herein are methods for treating or preventing acne vulgaris and inflammatory conditions thereof comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds of Formula I in combination with one or more therapeutic agents selected from alcohol, benzoyl peroxide, clindamycin, tretinoin, vitamin E, vitamin A and its derivatives, tetracycline, isotretinoin, vitamin C, vitamin D, chaparral, dandelion root, licoric root, Echinacea, kelp, cayenine, sassafras, elder flowers, pantothenic acid, para amino benzoic acid, biotin, chohn, inositol, folic acid, calcium, magnesium, potassium, vitamin B6, zinc, carotenoid, azelaic acid, and other therapeutic agents, which can be used to treat acne or condition the skin
The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulfinyl, sulfonyl group or -NRa-, wherein Ra can be hydrogen, alkyl, alkenyl, alkynyl cycloalkyl or aryl This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like Alkyl groups may be substituted further (referred herein as "substituted alkyl") with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl (for R6-R9, alkyl is not substituted with aryl), heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)Rk, -NRpRq, -C(=O)NRpRq, -NHC(=O)NRpRq, -C(=O)heteroaryl, C(=O)heterocyclyl, -0-C(=O)NRpRq {wherein RP and Rq are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, hydroxyamino, alkoxyamino or S(O)mR66 (wherein m is an integer from 0-2 and R66 is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl) Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, -NRpRq, -C(=O)NRpRq, -OC(=O)NRpRq -NHC(=O)NRfpRq (wherein Rpand Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and S(O)mR66 (wherein m is an integer from 0-2 and R66 are the same as defined earlier), or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NRa-{wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORp (wherein Rp is the same as defined earlier), S(O)mR66 (wherein m is an integer from 0-2 and R66 is as defined earlier), or -C(=O)NRpRq (wherein RP and Rq are as defined earlier)} Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, -NRpRq, -C(=O)NRpRq, -O-C(=O)NRpRq (wherein RP and Rq are the same as defined earlier) hydroxy alkoxy, halogen, CF3, cyano, and S(O)mR66 (wherein m is an integer from 0-2 and R66 is same as defined earlier), or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above
The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or
geminal geometry It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulfinyl, sulfonyl and -NRa-, wherein Ra can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom Alkenyl groups may be substituted further (referred to herein as "substituted alkenyl") with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC(=O)Rp, -NRpRq, -C(=O)NRpRq, -NHC(=O)NRpRq, -0-C(=O)NRpRq (wherein Rp and Rq are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, keto, carboxyalkyl, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, hydroxyamino, alkoxyamino, nitro, or SO2R66 (wherein R66 are is same as defined earlier) Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1 -3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF3, cyano, -NRpRq, -C(=O)NRpRq, -0-C(=O)NRpRq (wherein Rpand Rq are the same as defined earlier) and -SO2R66 (where R66 is same as defined earlier) Groups such as ethenyl or vinyl (CH=CH2), 1-propylene or allyl (-CH2CH=CH2), iso-propylene (-C(CH3)=CH2), bicyclo[2 2 ljheptene, and the like, exemplify this term
The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated
hydrocarbon, having from 2 to 20 carbon atoms It can be optionally interrupted by atom(s) or
group(s) independently chosen from oxygen, sulfur, phenylene, sulfinyl, sulfonyl and -NRa-,
where Ra can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl In the event that alkynyl is
attached to a heteroatom, the triple bond cannot be alpha to the heteroatom Alkynyl groups
may be substituted further (referred to herein as "substituted alkynyl") with one or more
substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, oxo,
thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy,
aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, heterocyclyl,
heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NHC(=O)RP -NRpRq, -
NHC(=O)NRpRq, -C(=O)NRpRq, -O-C(=O)NRpRq (wherein RP and Rq are the same as defined
earlier), S(O)mR66 (wherein m is an integer from 0-2 and R66 is as defined earlier) Unless
otherwise constrained by the definition, alkynyl substituents optionally may be substituted
further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy,
halogen, CF3, -NRpRq, -C(=O)NRpRq, -NHC(=O)NRpRq, -C(=O)NRpRq (wherein Rp
and Rq are the same as defined earlier), cyano, or S(O)mR66 (wherein m is an integer from 0-2 and R66 is same as defined earlier) Groups such as ethynyl, (-C^CH), propargyl (or propynyl, -CFTJC^CH), and the like exemplify this term
The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3
to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may
optionally contain one or more olefinic bonds, unless otherwise constrained by the definition
Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl,
cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including
adamantanyl, and bicyclo [2 2 1] heptane, or cyclic alkyl groups to which is fused an aryl group,
for example, indane, and the like Spiro and fused ring structures can also be included
Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl,
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy,
carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl,
aminocarbonylamino, -NRpRq, -NHC(=O)NRpRq, -NHC(=O)Rp, -C(=O)NRpRq, -O-
C(=O)NRpRq (wherein RP and Rq are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or S(O)mR66 (wherein m is an integer from 0-2 and R66 is same as defined earlier) Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRpRq, -C(=O)NRpRq, -NHC(=O)NRpRq, -O-C(=O)NRpR<1 (wherein Rp and Rq are the same as defined earlier), cyano or S(O)mR66 (wherein m is an integer from 0-2 and Re6 is same as defined earlier) As used herein the term "halogen or halo" refers to fluorine, chlorine, bromine or iodine
As used herein the term "hydroxyl protected" includes, but is not limited to, acyl, aroyl, alkyl, aryl, butyldiphenylsilyl, methoxymethyl and methylthiomethyl, and the like
As used herein the term "thio" refers to the group -SH
The term "alkoxy" denotes the group O-alkyl or O-cycloalkyl, wherein alkyl and cycloalkyl are the same as defined above Examples of alkoxy include, but are not limited to, methoxy, ethoxy, cyclopentoxy, and the like
As used herein the term "thioalkyl" refers to -SR5 wherein R5 is alkyl or cycloalkyl
As used herein the term "haloalkyl" refers to alkyl of which one or more hydrogen(s) is/are replaced by halogen
The term "aryl" herein refers to aromatic system having 6 to 14 carbon atoms, wherein
the ring system can be mono-, bi- or tricyclic and are carbocychc aromatic groups For example,
aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring and the
like, optionally substituted with 1 to 3 substituents selected from halogen (e g, F, CI, Br, I),
hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COORs
(wherein Rs is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl),
NHC(=O)Rp, -NRpRq, -C(=O)NRpRq, -NHC(=O)NRpRq, -0-C(=O)NRpRq (wherein Rp
and Rq are the same as defined earlier), S(O)mR66 (wherein m is an integer from 0-2 and R66 is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term
The term "aralkyl," unless otherwise specified, refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined above Examples of aralkyl include, but are not limited to, benzyl, napthylmethyl, phenethyl and phenylpropyl, and the like
The terms "heterocycle" or "heterocyclyl," unless otherwise specified, refers to a non-
aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon
atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are
benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted,
wherein the substituents are selected from halogen (e g ,¥, CI, Br, I), hydroxy, alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, acyl, amino, optionally substituted aryl, alkoxy, alkaryl, cyano,
nitro, oxo, carboxy, guanidine, haloalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, heteroaryl, -CORp, -0-C(=O)Rp, -0-C(=O)ORp -
C(=O)NRpRq, S(0)mR66, -0-C(=O)NRpRq, nitro, -NHC(=O)NRpRq, -NRpRq (wherein
m, Re6 RP and Rq are as defined earlier), -NHCORp, -NHSO2Rp, and -SO2NHRp, mercapto or thioalkyl
Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i e ,
carbon or heteroatom in the ring Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s) Examples of heterocycles include, but not limited to, azabicyclohexyl, azetidinyl, benzoimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothiazmyl, benzotnazolyl, benzoxazinyl, carbaxolyl, dihydrobenzofuryl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dihydroindolyl, dihydroisoxazolyl, dihydropyndinyl, dioxanyl dioxolanyl, furyl, homopipendinyl, lmidazolyl, lmidazohnyl, lmidazohdinyl, lmidazopyndinyl, indolinyl, indolyl, isoindole 1,3-dione, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morphohnyl, napthyndinyl, oxazohdinyl, oxazolyl, phenoxazinyl, phenothiazinyl, piperazinyl, pipendinyl, punnyl, pyrazinyl, pyrazohnyl, pyrazolyl, pyndinyl, pyndyl, pynmidinyl, pyrrohdinyl, pyrrohnyl, pyrrolyl, pyrrolopyndinyl, quinohnyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiazohdinyl and thiazolyl, and thienyl and the like
As used herein the term "(heterocyclyl)alkyl" refers to heterocycle which is bonded to an alkylene chain, wherein heterocyclyl and alkyl are the same as defined above Examples of heterocycle alkyl include, but are not limited to, isothiazolidinyl ethyl, isothiazolyl propyl, pyrazinyl methyl, pyrazohnyl propyl and pyndyl butyl, pyndyl methyl and the like
As used herein the term "polymorphs" refers to all crystalline forms and amorphous forms of the compounds described herein In addition, some of the compounds described herein may form solvates with water (i e , hydrate, hemihydrate or sesquihydrate) or common organic solvents Such solvates are also encompassed within the scope of this invention
The phrase "pharmaceutically acceptable salts" denotes salts of the free base, which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable Suitable pharmaceutically acceptable salts may be prepared from an inorganic or organic acid Example of such inorganic acids include, but not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous (nitrite salt), carbonic, sulfuric, phosphoric acid and like Appropriate organic acids include, but not limited to, aliphatic, cycloahphatic, aromatic, heterocyclic, carboxyhc and sulfonic classes of organic acids, for example, formic, acetic propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumenc, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandehc, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic,
algenic, beta-hydroxybutync, cyclohexylaminosulfonic, galactanc and galacturonic acid and the hke
The term pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any
type
The compounds of present invention include stereoisomers The term "stereoisomer" refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space These include enantiomers, diastereomers, geometrical isomers, atropisomer and comformational isomers Geometric isomers may occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity An enantiomer is a stereoisomer of a reference molecule that is the nonsupenmposable mirror image of the reference molecule A diastereomer is a stereoisomer of a reference molecule that has a shape that is not the mirror image of the reference molecule An atropisomer is a conformation of a reference compound that converts to the reference compound only slowly on the NMR or laboratory time scale Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about o bonds, and are often rapidly interconverting at room temperature Racemic mixtures are also encompassed within the scope of this invention
Detailed Description of the Invention
Compounds described herein may be prepared by techniques well known to one of ordinary skill in the art In addition, compounds described herein may also be prepared by the following reaction sequences as depicted in Scheme I below
(Scheme Removed)
Compounds of Formula 11 can be prepared according to Scheme I Thus, clarithromycin of Formula 2 can be hydrolyzed to form a compound of Formula 3 The compound of Formula 3 can be protected by reacting with one or more reagents of Formula R^O or R!X (wherein X is halogen) to form a compound of Formula 4 (wherein R1=COPh) The compound of Formula 4 can be reacted with one or more reagents, for example, tnphosgene, ethylene dicarbonate or a mixture thereof, to form a compound of Formula 5 The compound of Formula 5 can be reacted with one or more organic bases (for example, tetramethyl guanidine, tnmethylamine or mixtures thereof) to form a compound of Formula 6 The compound of Formula 6 can be oxidized to form a compound of Formula 7 The compound of Formula 7 can be desmethylated at the 3'-N-dimethyl group to form a compound of Formula 8 The compound of Formula 8 can be alkylated by reacting with one or more reagents of Formula R2CHO, R22CO or R2X (wherein X is halogen) to form a compound of Formula 9 (wherein R2 is the same as defined earlier) The compound of Formula 9 can be reacted with N,N'-carbonyldnmidazole to form a compound of Formula 10 The compound of Formula 10 can be reacted with a compound of Formula RWNH2
to form a compound of Formula 11 (wherein W and R are the same as defined earlier) The compound of Formula 11 can be deprotected to form a compound of Formula 12
Clarithromycin of Formula 2 can be hydrolyzed in the presence of an inorganic or organic acid, for example, hydrochloric acid, sulfuric acid or dichloroacetic acid
The compound of Formula 3 can be hydroxyl protected by reacting with one or more reagents of Formula R12O or R1X in one or more solvents, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate or mixtures thereof The protection reactions can also be carried out in the presence of one or more organic bases, for example, tnethylamine, dnsopropylethylamine, pyridine, tnbutylamine, 4-(N-dimethylamino)pyndine or mixtures thereof
The compound of Formula 4 can be reacted to form compounds of Formula 5 in one or more solvents, for example, chloroform, dichloromethane, carbon tetrachloride, dichloroethane or mixtures thereof These reactions can also be carried out in the presence of one or more organic bases, for example, tnethylamine, dnsopropyl ethylamine, pyridine, tnbutylamine, 4-(N-dimethylamino)pyndine or mixtures thereof
Compounds of Formula 5 can be reacted with one or more organic bases in one or more solvents, for example, dimethylformamide, tetrahydrofuran, dimethylsulfoxide or mixtures thereof
Compounds of Formula 6 can be oxidized by reacting with one or more oxidizing agents, for example, Dess-Martin penodinane, N-chlorosuccinimide, pyndinium chlorochromate, Swern Oxidation reagent (oxalyl chloride and dimethylsulfoxide), Pfitzner-Moffatt Oxidation reagent (dicyclohexylcarbodnmide and dimethylsulfoxide), Jones Oxidation reagent (chromic acid, aqueous sulfuric acid and acetone), pyndinium dichromate, l-ethyl-3-(3-dimethylaminopropyl)carbodnmide hydrochloride or mixtures thereof N-Chlorosuccinamide can be used in combination with dimethyl sulfide and 1-ethy 1-3(3-dimethylaminopropyl)carbodiimide hydrochloride can be used in combination with dimethylsulfoxide Compounds of Formula 6 can also be oxidized in one or more solvents, for example, chloroform, dichloromethane, carbon tetrachloride, dimethylsulfoxide, dichloroethane or mixtures thereof
Compounds of Formula 7 can be desmethylated in the presence of one or more desmethylating agents, for example, N-iodosuccimmide iodine in acetic acid, dnsopropylazodicarboxylate or mixtures thereof Such desmethylation reactions can also be carried out in one or more solvents, for example, acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate or mixtures thereof
Desmethylation reactions can be quenched in the presence of one or more quenching agents, for example, sodium bisulfite, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate or mixtures thereof
Compounds of Formula 8 can be alkylated with one or more reagents of Formula R2CHO, R22CO or R2X in one or more solvents, for example, dimethylformamide, acetonitrile, methanol, acetone, tetrahydrofuran or mixtures thereof Alkylation reactions can also be carried out in the presence of one or more inorganic or organic bases, for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium hydride, pyridine, tnethylamine, sodium acetate, sodium thiosulfate, dnsopropyl ethylamine or mixtures thereof Alkylation reactions can also be carried out in the presence of one or more reducing agents (for example, sodium cyanoborohydnde, sodium borohydnde, sodium tnacetoxyborohydnde or mixtures there) and in the presence of one or more organic acids (for example, acetic acid or dichloroacetic acid in a solvent, for example, methanol, ethanol, propanol, isopropanol or mixtures thereof)
Compounds of Formula 9 can be reacted with N,N'-carbonyldnmidazole in one or more solvents, for example, dimethylformamide, acetonitrile, tetrahydrofuran or mixtures thereof This reaction can also be carried out in the presence of one or more inorganic bases, for example, sodium hydrogen carbonate, sodium acetate, sodium thiosulfate, potassium carbonate, cesium carbonate or sodium hydride
Compounds of Formula 10 can be reacted with compounds of Formula RWNH2 in one or more solvent systems, for example, acetonitnle/water, dimethylformamide/water, dimethylformamide or combinations thereof
Compounds of Formula 11 can be deprotected in one or more alcohols, for example, methanol, ethanol, propanol, isopropanol or mixtures thereof
In the above sechemes, where specific reagents, for example, bases, acids oxidizing agents, solvents, etc , are described, it is to be understood that other reagents, e g, bases, acids, oxidizing agents, solvents, etc , known to one of ordinary skill in the art may be used Similarly, reaction temperatures and durations may be adjusted according to the desired needs without undue experimentation and well within the abilities of one of ordinary skill in the art All the epimers, unless otherwise specified in the above schemes, are also encompassed within the scope of the invention
Compounds of the present invention useful for such purpose are listed below
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(2-pyndin-3-yl-methyl-benzimidazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 1),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-pyndin-3-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 2),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(imidazo[4,5-b]pyndin-l-yl)-butyl)-imino)] erythromycin A (Compound No 3),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3,4-dihydro-2H-quinolin-1 -yl)-butyl)-imino)] erythromycin A (Compound No 4),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-tetrazol-1 -yl-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 5),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-furan-3-yl-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 6),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-thiophen-2-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 7),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-furan-2-yl-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 8),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-pyrazin-2-yl-thiazol-2-yl)-butyl)-imino)] erythromycin A (Compound No 9),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyndin-3-yl-thiazol-2-yl)-butyl)-imino)] erythromycin A (Compound No 10),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(6-pyrazol-1 -y l-pyndin-3-y l)-buty l)-imino)] erythromycin A (Compound No 11),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(6-imidazol-1 -yl-pyndin-3-yl)-buty l)-imino)] erythromycin A (Compound No 12),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosammyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-amino phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 13),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(6-pyrrol-1 -yl)-pyndin-3 -y l)-imidazol-1 -yl)-buty 1)-imino)] erythromycin A (Compound No 14),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(6-pyrrol-1 -yl-pyndin-3-yl)-butyl)-imino)] erythromycin A (Compound No 15),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(2-pyrrol-l-yl-thiazol-5-yl)-butyl)-imino)] erythromycin A(CompoundNo 16),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-([l,4']-biimidazol-l'-yl)-butyl)-imino)] erythromycin A (Compound No 17),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-thiaophen-2-y l-pyndin-3-y l)-butyl)-imino)] erythromycin A (Compound No 18),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-methy 1-3-aminopheny l)-imidazol-1 -y l)-buty 1)-imino)] erythromycin A (Compound No 19),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,1 l-[oxycarbonyl-((4-(4-(3-(N,N-dicyclopropyl-amino)-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A(Compound No 20),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-(N,N-dimethyl-amino)-phenyl)-imidazol-1 -y 1)-butyl)-imino)] erythromycin A (Compound No 21),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12, ll-[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-mcotinamido)-butyl)-imino)] erythromycin A(Compound No 22),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(2-pyrrol-1 -yl-thiazol-5-yl)-imidazol-1 -y l)-butyl)-immo)] erythromycin A (Compound No 23),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(N-(thiazol-2-yI)-benzamido)-buty l)-imino)] erythromycin A (Compound No 24),
5-0-(3'-N-desmethyl-3'-N-ethyI)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(3-(N-acetyl-amino)-phenyl)-imidazol-l-yl)-butyl)-lmino)] erythromycin A(Compound No 25),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(3-(N-isopropyl-amino)-phenyl)-imidazol-1 -yl)-buty 1)-lmino)] erythromycin A(Compound No 26),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosy]-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(4-fluoro-pheny l)-imidazol-1 -y l)-butyl)-imino)] erythromycin A (Compound No 27),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosamrnyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(4-methoxy-pheny l)-imidazol-1 -yl)-buty l)-imino)] erythromycin A (Compound No 28),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(benzthiazol-2-yl)-benzamido)-butyl)-imino)] erythromycin A (Compound No 29),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-isonicotinamido)-buty l)-imino)] erythromycin A (Compound No 30),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(N-(5-methyl-pyndin-2-yl)-benzamido)-butyl)-imino)] erythromycin A (Compound No 31),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(2-amino-pynmidin)-5-yl)-imidazol-l-yl l)-butyl)-lmino)] erythromycin A (Compound No 32),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(2-amino-pyndin)-5-yl)-imidazol-l-yl l)-butyl)-imino)] erythromycin A (Compound No 33),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(2-amino-pyndin)-4-yl)-imidazol-l-yl l)-butyl)-imino)] erythromycin A (Compound No 34),
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(2-amino-pynmidin)-5-yl)-pyrazol-1 -yl l)-butyl)-lmino)] erythromycin A (Compound No 35),
or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof
The compounds described herein are pharmacologically active against gram-positive, gram-negative and anaerobic bacteria and accordingly, are useful as antibacterial agents for treating bacterial infections in a patient in need thereof, for example, in a human or an animal Because of their antibacterial activity, the compounds described herein may be administered to an animal for treatment orally, topically, rectally, internasally, or by parenteral route Pharmaceutical compositions described herein comprise pharmaceutically effective amounts of compounds described herein formulated together with one or more pharmaceutically acceptable carriers, excipients or diluents
Solid form preparations for oral administration include capsules, tablet, pills, powder, granules, cachets and suppositories For solid form preparations, active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carrier, for example, sodium citrate, dicalcium phosphate and/or fillers or extenders (for example, starches, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof), binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrohdinone, sucrose, acacia or mixtures thereof, disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates, sodium carbonate or mixtures thereof, absorption acceletors, for example quaternary ammonium compounds, wetting agents, for example, cetyl alcohol, glycerol mono stearate or mixtures thereof, adsorbants, for example, Kaolin, lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium luaryl sulfate or mixtures thereof, or mixtures thereof
Capsules, tablets or pills may also comprise buffering agents
Tablets, capsules, pills or granules can be prepared using one or more coatings or shells, for example, enteric coatings or other coatings known to one of ordinary skill in the art
Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs In such liquid form preparations, active compounds can be mixed with water or one or more other solvents, solubilizing agents or emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol, fatty acid
esters of sorbitan or mixtures thereof Oral compositions can also include one or more adjuants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents or mixtures thereof
Injectable preparations, for example, sterile injections, and aqueous suspensions may be formulated according to methods known to one of ordinary skill in the art, and in particular, using one or more suitable dispersing or wetting and suspending agents Acceptable vehicles and solvents that may be employed include one or more of water, Ringer's solution, isotonic sodium chloride or mixtures thereof
Dosage forms for tropical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches Active compounds can be admixed under sterile condition with one or more pharmaceutical ly acceptable carriers and optionally any preservatives or buffers as may be required Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention
Pharmaceutical preparations may be in unit dosage form In unit dosage form, the preparations can be subdivided into unit doses containing appropriate quantities of active components Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams or any combination and number of such packaged forms
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims
Examples Example 1 Preparation of compound of Formula 2
Clarithromycin (25 gm, 33 4 mmol) was added to aqueous solution of hydrochloric acid at an ambient temperature in portion wise The reaction mixture was neutralized with solid sodium bicarbonate and the aqueous layer was extracted with ethyl acetate Organic layer was
washed with water, brine, and dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to afford crude product The crude product was crystallized from ethyl acetate and hexane mixture
Example 2 Preparation of compound of Formula 3
Benzoic anhydride (2 5 equiv) followed by tnethylamine (6 equiv) was added to a solution of compound of Formula 2 (1 equiv) in dichloromethane and stirred at an ambient temperature for about 40 hours The reaction was quenched by addition of sodium bicarbonate solution The aqueous layer was extracted with dichloromethane, washed successively with water, brine, and dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to give crude product The crude product obtained was crystallized from ethyl acetate and hexane mixture
Example 3 Preparation of compound of Formula 4
Tnphosgene (1 5 equiv) was added to a solution of compound of Formula 3 (1 equiv) in dichloromethane and pyridine was slowly added (15 equiv) to it The reaction mixture was stirred for about 4 hours and the reaction was quenched by addition of ice-cold water Reaction mixture was diluted with dichloromethane and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product
Example 4 Preparation of compound of Formula 5
Tetramethyl guanidine (2 2 equiv ) was added to a solution of compound of Formula 4 (1 equiv) in dimethylformamide and heated at about 70 °C, stirred for about 10 hours The reaction mixture was cooled to an ambient temperature Organic layer was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the desired product
Example 5 Preparation of compound of Formula 6
Dess-Martine Penodinane (2 5 equiv ) was added to a solution of compound of Formula 5 (1 equiv ) in dichloromethane and refluxed for about an hour The reaction was cooled to an ambient temperature and quenched by addition of saturated aqueous potassium carbonate
solution followed by saturated sodium thiosulphate solution and stirred Aqueous layer was separated and extracted with dichloromethane The dichloromethane layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product
Example 6 Preparation of compound of Formula 7
N-iodosuccinimide (2 equiv) was added to a solution of compound of Formula 6 (1 equiv) in dry acetonitnle dichloromethane (2 1) at about 0 °C and the reaction mixture was allowed to attain an ambient temperature and stirred The reaction mixture was stirred with sodium bisulphite solution followed by stirring with sodium carbonate solution Dichloromethane was evaporated under reduced pressure The aqueous layer was extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous sodium sulphate and then the solvent was removed under reduced pressure to afford the desired product
Example 7 Preparation of compound of Formula 8
Solid sodium hydrogen carbonate (5 equiv) and ethyl iodide (6 equiv) were added to a solution of compound of Formula 7 (1 equiv ) in acetonitnle under argon at an ambient temperature and stirred for about 24 hours The reaction was quenched by the addition of water, diluted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield a crude product The crude product was purified by silica gel column chromatography (thoroughly neutralized with tnethylamine) using 10-15% acetone in hexane to afford the desired product
Example 8 Preparation of compound of Formula 9
N, N'-carbonyldnmidazole (3 equiv ) was added to a solution of compound of Formula 8 (1 equiv) in dimethylformamide tetrahydrofuran (3 2) at an ambient temperature, cooled, and sodium hydride (3 equiv) was added in portions and was stirred The reaction mixture was quenched by addition of water It was extracted with ethyl acetate The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product
Example 9 Preparation of compound of Formula 10
The compound of Formula 9 (1 equiv) and R-W-NH2 (2 equiv) were taken in water in acetonitnle and heated at 70 °C, stirred for about 20 hours, reaction mixture was cooled to attain an ambient temperature and acetonitnle was removed under reduced pressure The resulting residue was taken in ethyl acetate and washed with water, brine, dried over anhydrous sodium sulphate, and filtered The filtrate was collected and concentrated under reduced pressure The compound was purified by silica gel column chromatography (thoroughly neutralized with tnethylamine) using 25-30% acetone in hexane to afford the desired product
Example 10 Preparation of compound of Formula 11
The compound of Formula 10 was taken in methanol and refluxed The reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure The compound was purified by silica gel column using 2-10% methanol in dichloromethane to afford the desired product
The following compounds were prepared following the procedures described above
Compound No 1 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(2-pyndin-3-yl-methyl-benzimidazol-l-yl)-butyl)-immo)] erythromycin A, Mass (M+l) 890 54, M P 170-173 (in °C)
Compound No 2 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyndin-3-yl-imidazol-1 -yl)-butyl)-lmino)] erythromycin A, Mass (M+l) 826 6, M P 61-62 (in °C)
Compound No 3 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(imidazo[4,5-b]pyndin-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 800, MP 108-110 (in°C)
Compound No 4 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3,4-dihydro-2H-quinolin-l-yl)-butyl)-lmino)] erythromycin A, Mass (M+l) 814 79, MP 75-77 (in °C)
Compound No 5 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-tetrazol-1 -y 1-imidazol-1 -y l)-buty 1)-imino)] erythromycin A, Mass(M+l) 8174,MP 109-111 (in °C)
Compound No 6 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-furan-3-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 815 4, M P 105-107 (in °C)
Compound No 7 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-thiophen-2-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 8314,MP 113-115 (in °C)
Compound No 8 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-O-methy 1-3-oxo-12, ll-[oxycarbonyl-((4-(4-furan-2-yl-imidazol-l-yl)-butyl)-lmino)] erythromycin A, Mass (M+l) 815 4, MP 101-103 (in °C)
Compound No 9 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-pyrazin-2-yl-thiazol-2-yl)-butyl)-lmino)] erythromycin A, Mass (M+l) 844 4, M P 70-71 (in °C)
Compound No 10 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-pyndin-3-yl-thiazol-2-yl)-butyl)-lmmo)] erythromycin A, Mass (M+l) 843 4, M P 86-87 (in °C)
Compound No 11 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(6-pyrazol-1 -yl-pyndin-3-yl)-butyl)-lmino)] erythromycin A, Mass (M+l) 826 4, MP 93-94 (in °C)
Compound No 12 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosy l-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(6-imidazol-1 -yl-pyndin-3-y l)-butyl)-lmino)] erythromycin A, Mass (M+l) 826 4, MP 98-99 (in °C)
Compound No 13 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-amino phenyl)-imidazol-1 -y 1)-butyl)-imino)] erythromycin A, Mass (M+l) 840 4, M P 89-91 (in °C)
Compound No 14 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(6-pyrrol-l -yl)-pyndin-3-yl)-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 891 5, M P 91-92 (in °C)
Compound No 15 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(6-pyrrol-l-yl-pyndin-3-yl)-butyl)-lmino)] erythromycin A, Mass (M+l) 825 4, M P 95-96 (in °C)
Compound No 16 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(2-pyrrol-1 -yl-thiazol-5-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 831 3, M P 87-88 (in °C)
Compound No 17 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-([l,4']-bnmidazol-r-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 815 5, MP 79-80 (in °C)
Compound No 18 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-O-methy 1-3-oxo-12, ll-[oxycarbonyl-((4-(4-thiaophen-2-yl-pyndin-3-yl)-butyl)-lmino)] erythromycin A, Mass (M+l) 842 3, M P 89-91 (in °C)
Compound No 19 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-(4-methyl-3-aminophenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 854 5, M P 103-105 (m °C)
Compound No 20 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-(3-(N,N-dicyclopropyl-ammo)-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 920 5, M P 96-98 (in °C)
Compound No 21 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-(N,N-dimethyl-amino)-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 868 5, M P 96-97 5 (m °C)
Compound No 22 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-nicotinamido)-butyl)-imino)] erythromycin A, Mass (M+l) 886 3, MP 114-115 (in °C)
Compound No 23 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-(2-pyrrol-l-yl-thiazol-5-yl)-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 897 4, M P 117-118 (in °C)
Compound No 24 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-benzamido)-butyl)-imino)] erythromycin A, Mass (M+l) 885 4, M P 103-105 (in °C)
Compound No 25 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(3-(N-acetyl-amino)-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 882 5, M P 94-96 (in °C)
Compound No 26 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(3-(N-isopropyl-amino)-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 882 5, M P 86-88 (in °C)
Compound No 27 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(4-fluoro-pheny l)-imidazol-1 -yl)-butyl)-imino)] erythromycin A, Mass (M+l) 843 4, M P 92-95 (in °C)
Compound No 28 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(4-methoxy-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass (M+l) 855 4, M P 100-102 (in °C)
Compound No 29 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(benzthiazol-2-yl)-benzamido)-butyl)-imino)] erythromycin A, Mass (M+l) 935 5, M P 128-129 (in °C)
Compound No 30 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(N-(thiazol-2-y l)-isonicotinamido)-butyl)-imino)] erythromycin A, Mass (M+l) 886 4, M P 102-104 (in °C)
Compound No 31 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(5-methyl-pyndin-2-yl)-benzamido)-butyl)-imino)] erythromycin A, Mass (M+l) 893 5, M P 110-112 (in °C)
Compound No 32 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(2-amino-pynmidin)-5-yl)-imidazol-1-yl l)-butyl)-immo)] erythromycin A, Mass (M+l) 842 4, M P 124-125 (in °C)
Compound No 33 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(2-amino-pyndin)-5-yl)-imidazol-l-yl l)-butyl)-imino)] erythromycin A, Mass (M+l) 841 4, M P 97-99 (in °C)
Compound No 34 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-l 2,11 -[oxycarbonyl-(4-(4-(2-amino-pyndin)-4-yl)-imidazol-1 -yl l)-butyl)-imino)] erythromycin A, Mass (M+l) 841 4, M P 124-125 (in °C)
Compound No 35 5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-0-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(2-amino-pynmidin)-5-yl)-pyrazol-1 -yl l)-butyl)-imino)] erythromycin A, Mass (M+l) 842 6, M P 108-110 (in °C)
Example 11 Pharmacological activity
Compounds described herein displayed antibacterial activity in vitro especially against strains that are resistant to macrohdes either due to efflux (mef strains) or nbosomal modification (erm) strains These compounds are useful in treating community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections, bone and joint infections, and other bacterial infections, for example, mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease
Minimum inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art
Procedure
Medium
a) Cation adjusted Mueller Hinton Agar (MHA-Difco)
b) Trypticase Soya Agar (TSA)
Inoculum preparation
Cultures were streaked on TSA for aerobic cultures and MHA with 5 % sheep blood for fastidious cultures Aerobic cultures were incubated at 37 °C for about 18-24 hours Fastidious
cultures were incubated CO2 incubation (5% CO2) at 37 °C for about 18-24 hours Three to four well-isolated colonies were taken and saline suspensions were prepared in sterile densimat tubes The turbidity of the culture was adjusted to 0 5-0 7 Mc Farland standard (15x10 CFU/mL) The cultures were diluted 10 fold in saline to obtain inoculum sizes of approximately 1-2 x 107 organisms/mL
Preparation of drug concentration
1 mg/mL concentration of stock solution of drugs was prepared in dimethylsulfoxide/distilled water/solvent given in National Committee for Clinical Laboratory Standards (NCCLS) manual Serial two-fold dilutions of the compounds and standard drugs were prepared as per NCCLS manual
The stock solution was changed according to the need of the experiment
Preparation of Agar Plates
Two mL of respective drug concentration was added to 18 mL of Molten Mueller Hinton agar to achieve the required range, for example 0 015 µg/mL - 16 µg/mL For fastidious cultures 1 mL of sheep blood was added in Molten Mueller Hinton agar
MHA and MHA with 5% sheep blood plates without antibiotic for each set were prepared for controls One MHA and MHA with 5% sheep blood plate without antibiotic for determining quality check for media was prepared
Preparation of Teflon template
1 µL of each culture on each plate was replicated with the help of a replicator 0 e , Denley's multipoint replicator) The spots were allowed to dry and the plates were incubated for about 18-24 hours at 37 °C Fastidious cultures were incubated at 37 °C in a CO2 incubator The results were noted comparing with the control plates
Endpoint definition
The concentration of drug at which there was complete disappearance of growth spot or formation of less than 10 colonies per spot was considered as Minimum Inhibitory Concentration (MIC)
The MICs of Quality Control (QC) strains were plotted on the QC chart for agar dilution method If the MICs were within the range, the results interpreted by comparing MICs of standards against all organisms with those of test compounds
Precautions & Quality Control Measures
Quality Control Strains
Staphylococcus aureus ATCC 29213
Enterococcus faecahs ATCC 29212
Eschericia coh ATCC 25922
Pseudomonas aeruginosa ATCC 27853
All 60 cultures were visually checked for purity
Media Control NCCLS disc diffusion assay using 10 µg discs of Gentamicin (Difco) against Pseudomonas aeruginosa ATCC 27853 A zone diameter of 16-21 mm was considered for optimum cation (Magnesium and Calcium) content of the media The diameter was plotted in the media QC chart
References
o National Committee for Clinical Laboratory Standards (NCCLS), Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition, Approved Standard M7-A5, Vol 20 No 2 (January 2000)
o National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Susceptibility Testing - Twelfth informational supplement, M 100-12, Vol 22 No 1 (January 2002)
Results Compounds of this invention were found to have activity againsts microbial strains, for example, Staphylococcus aureus Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhahs Streptococcus pyogenes enterococci species Helicobacter pylori E faecahs or combination thereof
Example 12 Pharmacological activity (Acne Vulgaris)
Method Minimum inhibitory concentration (MIC) of compound described herein and standard drugs are determined against clinical and ATCC isolates (n=6) of Propionibactenum acnes [Propionibactenum acnes I (Sensitive), Propionibactenum acnes II (Sensitive), Propionibactenum acnes 6523, Propionibactenum acnes ATCC 6919 and two isolates of Propionibactenum acnes (Resistant)] as per NCCLS guidelines (Ml 1-A5) by agar dilution method Brucella agar (Difco) with hemin (5 µg/ml) and vitamin Kl (1 µg/ml) supplemented with 5% (v/v) laked sheep blood is used as media Stock concentrations of standard drug are prepared in respective diluents as per NCCLS guidelines Stock solution (1 mg / ml) of NCEs is prepared in DMSO and serial two fold dilutions of drug are prepared and mixed with agar Inoculum is prepared from freshly grown isolates on brucella blood agar and their turbidity is adjusted to approximately 0 5 McFarland Replicate 1 71 of cultures on agar plate with the help of a replicator (Denley's multipoint replicator) All plates are incubated at 37°C for 48 hours in anaerobic jar under anaerobic condition created by using Anaxomat

WE CLAIM:
1 Compounds having the structure of Formula I,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof, wherein:
R1 is hydrogen or a hydroxyl-protecting group;
R2 is C2-C6 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocyclic)alkyl or COR4;
R4 is hydrogen, alkyl or aralkyl; W is (CH2)q, CR5R6, NR5 or S02;
q is an integer of from 2 to 10;
R5 and R6 are independently hydrogen or alkyl;
(CH2)q group is optionally interrupted by one or more of unsaturated bonds, oxygen, sulfur, CO, CS, SO2, NRi or combination thereof;
one or more hydrogen atoms of (CH2)q group is optionally replaced by halogen, alkyl, hydroxyl or alkoxy;
Ri is hydrogen, alkyl, alkenyl, alkynyl, COR2 or (CH2)mR2;
R.2 is alkyl, alkenyl, alkynyl, aryl, heterocycle;
m is an integer of from 2 to 4
R is R6NCOR7, aryl or heterocycle;
R6 and R7 are independently aryl or heterocycle;
R is alkyl, alkenyl or alkynyl;
R' is alkyl or -(CH2)r-U;
r is an integer of from 1 to 4;
U is alkenyl or alkynyl;
Z is oxygen, sulfur or NOR4;
R4 is the same as defined earlier.
2 The compounds of claim 1, wherein:
R1 is hydrogen;
R2 and R3 can be ethyl;
W is (CH2)q , wherein (CH2)q is the same as defined earlier;
R' is methyl;
Z is oxygen; and R is R6NCOR7,
(Structure Removed)
Xi to X3 are independently CH or N;
X4 to X8 are independently CH, CR3 or N;
X9 is O, S, N, NH or CH;
X10 is NH or S;
Ra is optionally substituted thienyl, furyl, pyrazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridinyl, fluoropyridinyl, chloropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrimidinyl, quinolinyl, pyrrolo-pyridyl, pyrrolo-thiazolyl or phenyl wherein optional substituent(s) can be methyl, halogen, methoxy, NR4R5 [wherein, R4 and R5 are independently hydrogen, methyl, isopropyl, cyclopropyl, acetyl];
R'a is hydrogen or furyl;
Rb is hydrogen or NR4R5 [wherein, R4 and R5 are independently hydrogen, methyl, isopropyl, cyclopropyl, acetyl];
Rc is hydrogen, optionally substituted thienyl, furyl, pyrazolyl, pyrazinyl, pyridinyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl or phenyl wherein optional substituent(s) can be methyl, halogen, methoxy, NR4R5 [wherein, R4 and R5 can be independently hydrogen, methyl, isopropyl, cyclopropyl, acetyl];
Rd is thienyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl or tetrahydrofuryl;
Re is (heterocyclic)alkyl;
R6 and R7 are independently aryl or heterocyclyl.
3 A compound selected from:
5 -0-(3 '-N-desmethy 1-3 '-N-ethy l)desosaminy 1-11,12-dideoxy-3 -O-decladinosy l-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-pyridin-3 -yl-methy 1-benzimidazol-1 -y l)-buty I)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-pyridin-3-yl-methyl-benzimidazol-1 -yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-pyridin-3-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino)] erythromycin A, 10856
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3,4-dihydro-2H-quinolin-1 -yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethy l)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-tetrazol-1 -y1-imidazol-1 -yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-furan-3-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-thiophen-2-yl-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-furan-2-yl-imidazol-1 -yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyrazin-2-yl-thiazol-2-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-pyridin-3-yl-thiazol-2-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(6-pyrazol-1 -yl-pyridin-3-y l)-buty l)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(6-imidazol-1 -yl-pyridin-3-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-amino phenyl)-imidazol-1 -yl)-buty 1)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-(6-pyrrol-l-yl)-pyridin-3-yl)-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(6-pyrrol-l-yl-pyridin-3-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-pyrrol-1 -yl-thiazol-5-y l)-buty l)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-([l,4']-biimidazol-r-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-thiaophen-2-yl-pyridin-3-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-(4-methyl-3-aminophenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-(3-(N,N-dicyclopropyl-amino)-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethy l-3'-N-ethy l)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-(N,N-dimethy l-amino)-pheny l)-imidazol-1 -yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-nicotinamido)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-(2-pyrrol-1 -yl-thiazol-5-y l)-imidazol-1 -y 1)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-benzamido)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(3-(N-acetyl-amino)-phenyl)-imidazol-1 -yl)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(3-(N-isopropyl-amino)-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(4-fluoro-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(4-methoxy-phenyl)-imidazol-l-yl)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-(N-(benzthiazol-2-yl)-benzamido)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(thiazol-2-yl)-isonicotinamido)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(N-(5-methyl-pyridin-2-yl)-benzamido)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-(2-amino-pyrimidin)-5-yl)-imidazol-1 -y 11)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(2-amino-pyridin)-5-yl)-imidazol-l-yl l)-butyl)-imino)] erythromycin A ,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(2-amino-pyridin)-4-yl)-imidazol-l-yl l)-butyl)-imino)] erythromycin A,
5-0-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 - [oxycarbony l-(4-(4-(2-amino-pyrimidin)-5-y l)-pyrazol-1 -yl 1)-butyl)-imino)] erythromycin A,
or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof.
4 A pharmaceutical composition comprising therapeutically effective amounts of one or more compounds of claim 1 together with one or more pharmaceutically acceptable carriers, excipients, diluents or mixture thereof.
5 A method for treating or preventing a condition caused by or contributed to by bacterial infection comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds of claim 1.
6 The method of claim 5, wherein the condition is selected from community acquired
pneumonia, upper or lower respiratory tract infections, skin or soft tissue infections, acne
vulgaris, hospital acquired lung infections, hospital acquired bone or joint infections,
mastitis, catether infection, foreign body, prosthesis infections, peptic ulcer disease or
combination thereof.
7 The method of claim 5, wherein the bacterial infection is caused by gram positive, gram negative or anaerobic bacteria.
8 The method of claim 7, wherein the gram positive, gram negative or anaerobic bacteria is selected from Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Propionibacterium acnes or Enterobactericeae.
9 The method of claim 8, wherein the bacterium is cocci.
10 The method of claim 9, wherein the cocci is drug resistant.
11 A process for preparing a compound of Formula 12,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof, wherein:
R2 is C2-C6 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocyclic)alkyl or COR4;
R4 is hydrogen, alkyl or aralkyl; W is (CH2)q, CR5R6, NR5 or S02;
q is an integer of from 2 to 10;
R and R are independently hydrogen or alkyl;
(CH2)q group is optionally interrupted by one or more of unsaturated bonds, oxygen, sulfur, CO, CS, SO2, NR1 or combination thereof;
one or more hydrogen atoms of (CH2)q group is optionally replaced by halogen, alkyl, hydroxyl or alkoxy;
Ri is hydrogen, alkyl, alkenyl, alkynyl, COR2 or (CH2)mR2;
R2 is alkyl, alkenyl, alkynyl, aryl, heterocycle;
m is an integer of from 2 to 4 R is R6NCOR7, aryl or heterocycle;
R6 and R7 are independently aryl or heterocycle; which method comprises the steps of: (a) hydrolyzing clarithromycin of Formula 2
(Formula Removed)
to form a compound of Formula 3
(Formula Removed)
(b) protecting the compound of Formula 3 with one or more reagents of Formula R12O or R1X (wherein X is halogen) to form a compound of Formula 4 (wherein R'=COPh)
(Formula Removed)
(c) reacting the compound of Formula 4 with one or more reagents selected from
triphosgene, ethylene dicarbonate or a mixture thereof to form a compound of
Formula 5 (Formula Removed)
(d) reacting the compound of Formula 5 with one or more organic bases selected from tetramethyl guanidine, trimethylamine or mixtures thereof to form a compound of Formula 6
(e) oxidizing the compound of Formula 6 to form a compound of Formula 7
(Formula Removed)
(f) desmethylating the compound of Formula 7 at the 3'-N-dimethyl group to form a compound of FormulaR (Formula Removed)
(g) alkylating the compound of Formula 8 with one or more reagents of Formula R2CHO, R22CO or R2X (wherein X is halogen) to form a compound of Formula 9
(Formula Removed)
(h) reacting the compound of Forn9ila 9 with N,N'-carbonyldiimidazole to form a compound of Formula 10 Formula Removed)
(i) reacting the compound of Formula 10 with a compound of Formula RWNH2to form a compound of Formula 11
(Formula Removed)
(j) deprotecting the compound of formula 11 to form a compound of Formula 12.