MACROLIDE DERIVATIVES AS ANTIBACTERIAL AGENTS

Field of Invention

The present invention provides macrolide derivatives, which can be used as antibacterial agents. Compounds disclosed 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, Corynebacterium, Bacillus, Enterobactericeae or any combination thereof. Also provided, are the processes for preparing the compounds disclosed herein, pharmaceutical compositions containing compounds disclosed herein, and methods of treating bacterial infections.

Background of the Invention

First generation macrolides 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, Z et al, Am. J. Physiol, T&L, (1984), 688 Omura, S et al, J. Med. Chem., 30, (1987) 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.

Macrolides 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. Macrolides exhibit greater efficacy and

safety, have broader spectrum of activities, and are particularly effective against resistant pathogens; hence, macrolides have been developed as next generation macrolides.

U.S. Patent No. 5,008,249 discloses therapeutic method of stimulating digestive tract contractile motion in mammals with some novel semi-synthetic macrolides. However, there remains a need for novel macrolide 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 macrolide 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 disclosed 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 I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof, wherein: n is an integer from 2 to 7,

Ri and R _∑ can be independently hydrogen, hydroxy, 0C(=Z')VR ₇ , SO ₂ R ₇ , Formula A or R] and R ₂ together can form oxo or thio group;

Formula A wherein Z' can be oxygen or sulfur; V can be -W(CH ₂ )r ; k can be an integer of from 0 to 6; W can be no atom, -NRg- or oxygen; R ₇ can be alkyl, aryl, heterocyclyl or heteroaryl; Rs can be hydrogen or alkyl; alkylene chain OfW(CH ₂ V can be optionally substituted with alkyl, hydroxy or alkoxy; R ₉ is hydroxyl, alkoxy, -0(CH ₂ ) _P WR _b , -OC(O)N(R ₈ )(CH ₂ ) _d WR _b; . NHC0(CH ₂ ) _d WR _b or -OC(O)(CH ₂ ), WR _b (wherein R _b is heterocyclyl or heteroaryl; W is as defined earlier; p is an integer 0-5, d is integer 2-6 and t is an integer 1-6) and R ₁ O is hydrogen or hydroxy protecting group;

R' is Rio; wherein R ₁ O is defined previously;

R ₃ can be hydrogen, alkyl or -(CH ₂ ) _r -U; r can be an integer of from 1 to 4; U can be (un)substituted alkenyl or alkynyl;

T can be hydrogen, halogen, cyano or alkyl; Z is -N(Q)CH ₂ -, -N=C(Q)-, -N(Q)C(O)- or -N=C(OQ)- wherein, Q is hydrogen, alkyl, alkenyl, alkynyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl

R ₄ can be hydrogen, alkyl, -ORi ₀ , or -NH(CH ₂ ) _q Rn, wherein Rn is aryl or heteroaryl and q can be an integer between 0 to 4; R ₅ can be hydrogen, hydroxyl, -OCORio, -ORi ₀ wherein Ri ₀ is defined previously; Re can be alkyl, alkenyl or alkynyl; further, when Z is -N=C(Q)-, then Q, together with the carbon atom, to which it is attached and R ₄ forms a bridge as in Formula B

Formula B

R ₄ and R ₅ , together with their carbon atoms to which they are attached (C ₁₁ and C ₁₂ ), can form a group represented by Formula C

Formula C

Ri2 can be alkyl, hydroxy, phenoxy or together with the carbon to which it is attached form C=O; A can be -O- or -N-, and R^ is no atom when A is O and M-R ₁₄ , when A is N, wherein M can be alkenyl, -G(CH ₂ ) _d J, -CR _f R _g , -NR _f - or -SO ₂ {[wherein d is as defined earlier, G can be no atom, -CO, -CS, -SO ₂ or -NR _f , J can be no atom, or -N((R _f )(CH ₂ ) _r (wherein R _f and R _g can be independently hydrogen or alkyl and r is as defined earlier)]} ; R ₁₄ can be no atom, hydrogen, aryl, heterocyclyl or heteroaryl; or, R ₃ and R ₄ can, together with the carbon atoms at the 6- and 11 -position of the erythronolide skeleton, form a group represented by Formula D

L can be -CH ₂ -CH(Ri ₅ )-C(Ri ₆ )=CH-, -CH ₂ -CH(Ri ₇ )-

CH(R ₁₈ J-CH ₂ -, -CH ₂ -C(R ₁₆ )(Rn)-CH ₂ -CH ₂ - or , , wherein R ₁₅ and R ₁₆ are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocycloalkyl; Rj ₇ and Rig are independently selected from R15, -OR10, - SO ₂ Ri ₅ , -NHC(O)Ri ₅ , -NHC(O)N(R ₃ )(Ri ₅ ), -NHSO ₂ Ri ₅ or -NRnRi ₂ ; Ri6 and R _n taken together with the carbon atom to which they are attached are selected from C=O,C(OR ₆ ) ₂ , or C=N-O-Ri ₅ ; D is -0-, -N(Ri ₅ )-, -OC(O)-CH(Ri ₅ )-, 0-C(O)-N(Ri ₅ )-, -O- C(O)-O-, N(Ri ₅ >N=N-; C(R _I5 )=N-0- or CH(R ₁₅ )-NH-0-.

In another aspect, provided herein are compounds:

5-O-(3 ' -N-bis-demethyl-3 '-N-pyrrolidin- 1 -yl)-6-O- methyl-9-deoxo-9a-aza-9,9a- anhydro homoerythromycin A 9a,l 1-iminoether (Compound no. 1);

5-O-(3 ' -N-bis-demethyl-3 '-N-azetidin- 1 -yl)-6-O- methyl-9-deoxo-9a-aza-9,9a- anhydro homoerythromycin A 9a, 11 -iminoether {Compound no. 2);

5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-O-methyl-9 -deoxo-9a-aza-9a- homoerythromycin A (Compound no. 3);

5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-0-methyl-9 -deoxo-9a-aza-9a- methyl-9a-homoerythromycin A (Compound no. 4); 5-0-(3'-N-bis-demethyl-3'-N-ρyrrolidin-l-yl)-9-deoxo-9a-aza -9a-methyl-9a- homo-erythromycin A (Compound no. 5);

5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-9-deoxo-9a-aza -9a-methyl-9a- homoerythro-mycin A (Compound no. 6) or

5-O-(3'-N-bis-demethyl-3'-N-piperidin-l-yl)-9-deoxo-9a-a2 :a-9a-methyl-9a-homo- erythromycin A (Compound no . 7) . m yet another aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds disclosed 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 of compounds disclosed 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, hospital acquired lung infections, hospital acquired bone or joint infections, mastitis, catherei 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 or Enterobactericeae. In a another embodiment, the bacterium is cocci. In yet another embodiment, the cocci are drug resistant.

The following definitions apply to terms as used herein:

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, sulphinyl, sulphonyl group or -NR _0T , wherein R _« can be hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl, -C( ^~ O)ORx, SO _m Rψ or -C(K))NRxR _1T . 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 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, heterocyclyl, heteroaryl, (heterocyclyl)alkyl, cycloalkoxy, -CH=N-O(d _-6 alkyl), -CH=N-NH(C _{1 -6} alkyl), alkyl)-C, _-6 alkyl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, - NHC(=O)Rχ, -NR _λ R _π , -C(=O)NRxR _x , -NHC(=O)NR _λ R _λ -C(=O)heteroaryl, C(=O)hetero- cyclyl, -0-C(O)NRxR _1T {wherein R _λ and R _π are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or carboxy}, nitro or - SO _m R^ (wherein m is an integer from 0-2 and R^ is hydrogen, 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, -NRχR _π , - Ct=O)NR _x R _1T , -OC(=O)NR _λ R _ff ,-NHC(=O)NR _λ R _π , hydroxy, alkoxy, halogen, CF ₃ , cyano, and -SOmR,/,; or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NR ₀ T- (wherein R^, Rx, R _π , m and R^ are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, -NR _x R _1T , -C(O)NRxR _1T , -O-C(=O)NR _λ R _π , hydroxy, alkoxy, halogen, CF ₃ , cyano, and -SO _m R^ (wherein Rx, R _π , m and R^- are the 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 "alkylene," as used herein, refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms and one or more hydrogen

can optionally be substituted with alkyl, hydroxy, halogen or oximes. This term can be exemplified by groups such as methylene, ethylene, propylene isomers (e.g., -CH ₂ CH ₂ CH ₂ and -CH(CH ₃ )CH ₂ ) and the like. Alkylene may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryloxy, heteroaryloxy, aminosulfonyl, -COOR,/., -NHCC=O)R _x , - NR _x R^, -CC=O)NR _x R ₁ ,, -NHQ=O)NR _x R*, -C(=O)heteroaryl, C(=O)heterocyclyl, -O- Q=O)NR _x R*, nitro, -S(O) _1n Rx (wherein R _x , R _x , m and R ₁ /, are the same as defined earlier). Unless otherwise constrained by the definition, all substituents maybe further substituted by 1-3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, -COOR^, -NR _x R ₁₁ -, -

C(=0)NR _λ R _π , -OCt=O)NR _x R _1T , -NHCH))NR _x R ₁ , hydroxy, alkoxy, halogen, CF ₃ , cyano, and -S(O) _1n R^ (wherein R _x , R _v , m and R^ are the same as defined earlier). Alkylene can also be optionally interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NR ₀ , (wherein R^ is the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, acyl, aralkyl, alkoxy, hydroxy, carboxy, - OC(O)NR _x R _x , -CONH-, -C=O or -C=NOH (wherein R _x , R _π , m and R^ are the same as defined earlier). 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. Alkenyl groups can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR _o - (wherein R ₀₁ is the same as defined earlier). 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 with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, - NHQ=O)R _x , -NR _x R _π , -C(O)NR _x R _x , -NHCC=O)NR _x R ₁₁ , -O-C(=O)NRχR _π , 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 SO _m R^ (wherein R _x , R _π , m and R^ are as defined earlier). Unless

otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkoxy, halogen, -CF ₃ , cyano, -NR _x R ₁ , -Ct=O)NR _x R _7n -O-C(=O)NR _λ R _π and -SO _1n R^ (wherein R _x , R _x , m and R^ are as defined earlier). Groups, such as ethenyl or vinyl (CH=CH ₂ ), 1- propylene or allyl (-CH ₂ CH=CH ₂ ), iso-propylene (-C(CH ₃ )=CH ₂ ), bicyclo[2.2. l]heptene, and the like, exemplify this term.

The term "alkenylene" unless otherwise specified, refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 6 carbon atoms with cis, trans or geminal geometry. In the event that alkenylene is attached to the heteroatom, the double bond cannot be alpha to the heteroatom. The alkenylene group can be connected by two bonds to the rest of the structure of compound of Formula I. Alkenylene may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, -NHC(=0)R\, -NR _X R ₁ T, - Q=O)NR _x R ₁ , -NHC(=O)NR _λ R _ir ,-OC(=O)NR _λ R _ff (wherein R _x and R _π are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR^ (wherein Rψ is the same as defined earlier), arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, alkoxyamino, nitro, -S(O) _m Rψ (wherein R^ and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, - COOR^ (wherein R^ is the same as defined earlier), hydroxy, alkoxy, halogen, -CF ₃ , cyano, -NR _x R ₇ T, -Q=O)NR _x R _7T , -0C(=0)NR _λ R _π (wherein R _x and R _τ are the same as defined earlier) and -S(O) _1n R^ (wherein R^ and m are the same as defined earlier).

The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. Alkynyl groups can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR _o - (wherein R _a is the same as defined earlier). In the event that alkynyl groups are attached to a heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, 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, -NHQ=O)R _x , -NR _x R*, -NHC(=O)NR _λ R _π , - CC=O)NR _x R^ -0-CC=O)NR _x R _7T or -SO _m R^ (wherein R _x , R*, m and R^ are the same as defined earlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF ₃ , -NR _x R _1T , - and R^. are the same as defined earlier).

The term "alkynylene" unless otherwise specified, refers to a diradical of a triply- unsaturated hydrocarbon, preferably having from 2 to 6 carbon atoms. In the event that alkynylene is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom. The alkenylene group can be connected by two bonds to the rest of the structure of compound of Formula I. Alkynylene may further be substituted with one or more substituents such as alkyl, alkenyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, nitro, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroarylalkyl, -Q=O)NR _x R^ -OQ=O)NR _x R ₁ (wherein R _x and R _τ are the same as defined earlier),- S(O) _1n R ₁ /. (wherein R^ and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, -COOR ₁ /, (wherein R^, is the same as defined earlier), hydroxy, alkoxy, halogen, CF ₃ , -NR _x R ₁₁ -, -Q=O)NR _X R _T , - NHQ=O)NR _x R ₁ , -Cf=O)NR _x R _7T (wherein R _x and R _τ are the same as defined earlier), cyano, and -S(O) _1n R^ (wherein R ₁ /, and m are the same as defined earlier). 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, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, and the like or polycyclic ring structures such as, adamantyl, tricyclo[3.3.1.1]decane, bicyclo[2.2.2]octane, bicyclo[4.4.0]decane, bicyclo[4.3.0]nonane, bicyclo[3.3.0]octane, bicyclo[2.2.1]heptane and the like,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, -NR _x R _π , -NHC(O)NR _x R ₇ T, -NHCf=O)R _x , - C(O)NR _x R ₁ T, rήtro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or SO _m R ₁ ^ (wherein R _x , R _m m and R ₁ /, are the same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkoxy, halogen, CF ₃ , -NR _x R _7n , -Ct=O)NR _x R*, -NHC(O)NR _x R _7T5 -OC(O)NR _x R ₇ T, cyano or -SOmR ₁ /, (wherein R _x , R _π , m and R^ are the same as defined earlier). "Cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier. The term "alkoxy" denotes the group O-alkyl, wherein alkyl is the same as defined above.

The term "aryl," unless otherwise specified, refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic 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, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF ₃ , cyano, nitro, -CHO, OCF ₃ , -SCF ₃ , COOR^, NHCf=O)R _x , -NR _x R ₁ T, -C(O)NR _x R _π , -NHC(O)NR _x R _x , -0-C(O)NR _x R,, -SOmR^, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino, mercapto, halo alkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, thioalkyl, -C0NHR _π , -OCOR _π , -COR ₁ , -NHSO ₂ R _1T Or-SO ₂ NHR^ (wherein R _x , R _T , m and R^ are the same as defined earlier). Aryl groups 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 below. Examples of aralkyl groups include benzyl, ethylphenyl, propylphenyl, naphthylmethyl and the like.

The term "aralkenyl," unless otherwise specified, refers to alkenyl-aryl linked through alkenyl (wherein alkenyl is as defined above) portion and the alkenyl portion contains 1 to 6 carbon atoms and aryl is as defined below.

The term "aryloxy" denotes the group O-aryl, wherein aryl is as defined above. The term "carboxy," as defined herein, refers to -C(=O)OH.

The term "heteroaryl," unless otherwise specified, refers to an aromatic monocyclic or polycyclic (fused, spiro or bridged) ring system containing 1-8 heteroatom(s) independently selected from N, O or S optionally substituted with 1 to 4 substituent(s) selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, thioacyl, oxo, -CHO, -OCF ₃ , -CF ₃ , -SCF ₃ , carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NR _λ R _πj CH=NOH, -{CH ₂ ) _W C(=O)R,, {wherein w is an integer from 0-4 and R^ is hydrogen, hydroxy, OR _x , NR _λ R _π , -NH0R _« or -NHOH}, -C(=O)NR _X R* -NHC(=0)NR _λ R _π . -SO ₁₁₁ R^ -0-C(=0)NR _λ R _λ -0-C(O)R _x , or -0-C(=0)0R _λ (wherein m, R _τ are as defined earlier and R ₀ , is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups includes but are not limited to are benzimidazolyl, 1 ,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzo- triazolyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, napthyridinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, purinyl, pyrazinyl, pyrazolinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrrolopyridinyl, imidazolpyridinyl, quinolinyl, tetrahydrofuranyl, quinozinyl, quinolizinyl, 6//-pyrido-[l,2- α]pyrimidmyl, tetrahydropyranyl, thiazolidinyl, thiazolyl, thienyl, pyridazinyl, carbazolyl, isobenzofuranyl, thianthrene, triazinyl, furanyl, benzofuranyl, tetrazolyl, quinazolinyl, benzoxazinonyl, benzothiazinonyl and the like. The term "cycloalkenyl" refers to unsaturated carbocyclic ring having three to seven carbon atoms. One or more hydrogen of said alkenyl or alkynyl can be replaced by

halogen, hydroxy, cyano, or -NRsR ₆ , wherein R ₅ and R ₆ are selected from hydrogen and alkyl. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl and cyclobutenyl, and the like. Multiple cyclic structures are also included.

The term "halogen or halo" refers to fluorine, chlorine, bromine or iodine. The term "haloalkyl" refers to alkyl of which one or more hydrogen(s) is/are replaced by halogen.

The term "heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic or polycyclic ring (fused, spiro or bridged) system having 1 to 8 hetero atoms 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., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, optionally substituted aryl, alkoxy, alkaryl, cyano, nitro, oxo, -CHO, -OCF ₃ , -CF ₃ , -SCF ₃ , carboxy, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, -Q-C(O)R _x , -0-C(O)OR _x , -C(O)NR _x TU, SO _m R^, -O- C(O)NR _x R ₁ , -NHC(O)NR _λ R _π , -NR _λ R _π , mercapto, haloalkyl, thioalkyl, -COORψ, - COONHR _x , -COR _x , -NHSO ₂ R _x or SO ₂ NHR _x (wherein m, R^, R _x and R _π are as defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more double bonds. Such ring systems can be mono-, bi- or tricyclic. 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 heterocyclyl groups includes but are not limited to are tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl, isoxazolinyl, thiazolinyl, thiazolidinonyl, oxazolinyl or oxazolidinonyl, azabicyclo[3.1.0]hexyl, diazabicyclo[2.2.1]heptyl, azetidinyl, 1 ,4-benzo-dioxanyl, 1,3-benzodioxolyl, dihydrobenzofuryl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dihydroindolyl, dihydroisoxazolyl, dihydropyridinyl, dioxanyl, dioxolanyl, homopiperi- dinyl, imidazolinyl, imidazolidinyl, imidazopyridinyl, indolinyl, indolyl, isoindolel,3-dione, isothiazolidinyl, morpholinyl, napthyridinyl, oxazolidinyl, oxazolyl, phenoxazinyl, phenothiazinyl, piperazinyl, purinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyrimidinyl,

pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrrolopyridinyl, tetrahydropyranyl, tetrazolyl, thiazolidinyl and thiazolyl, and thienyl and the like.

"Heteroarylalkyl" refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are as defined earlier. "Heterocyclylalkyl" refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are as defined earlier.

"Acyl" refers to -Ct=O)R ₁ ^ wherein R^ is selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.

"Alkylcarbonyl" refers to -Ct=O)R^, wherein R^ is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.

"Alkylcarboxy" refers to -0-C(K))R^ _, wherein R^ is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.

"Amine," unless otherwise specified, refers to -NH ₂ . "Substituted amino" unless otherwise specified, refers to a group -N(R _k ) ₂ wherein each R _k is independently selected from the group hydrogen provided that both R _t groups are not hydrogen (defined as "amino"), alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, S(O) _1n R^ (wherein m and Rψ are the same as defined above), -C(=R _v )NRxR _y (wherein R _v is O or S & R _\ and R _y are the same as defined earlier) or NHC(=R _v )NR _y Rχ (wherein R _v , R _y and R _\ are the same as defined earlier). Unless otherwise constrained by the definition, all amino substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, carboxy, -COOR^, (wherein R^ is the same as defined earlier), hydroxy, alkoxy, halogen, CF ₃ , cyano, -C(=Rv)NR _λ Ry (wherein R _v is the same as defined earlier), -0(C-0)NR _λ R _y , -0C(=R _v )NR _λ R _y (wherein R _x , R _y and R _v are the same as defined earlier), -S(O) _1n R^ (wherein R^ and m are the same as defined above).

"Thio" refers to the group -SH.

"Thiocarbonyl" refers to -C(-S)H. "Substituted thiocarbonyl" refers to-C(=S)R^, wherein R^ is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, amine or substituted amine.

Unless otherwise constrained by the definition, all substituents optionally may be substituted further by 1-3 substituents selected from alkyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF ₃ , cyano, - C(=T)NRχR _π , -0(C=O)NR _x R _1T (wherein R _x , R^ and T are the same as defined earlier) and - OC(=T)NRxR, _r , -SO _1n R ₁ /. (wherein m and R^ are the same as defined earlier).

The term "hydroxy Protecting groups" refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Examples of such groups are found in T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3 ^rd Ed, John Wiley and Sons, New York, N.Y., which is incorporated herein by reference. The species of the hydroxy protecting group employed is not so critical so long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule. Examples of such hydroxyl protecting groups include, but are not limited to, acyl, aroyl, alkyl, aryl, butyldiphenylsilyl, methoxymethyl and methylthiomethyl, and the like.

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 or common organic solvents. Such solvates are also encompassed within the scope of this invention.

The term "pharmaceutically acceptable salts" refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, sulfuric, phosphoric acid, and the like. Appropriate organic acids include, but are not limited to aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic, 2-hydroxyethanesulfonic acid and the like.

The phrase "pharmaceutically acceptable earners" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating matenal 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, atropisomers and conformational isomers. All such isomeric forms of these compounds are expressly included in the present invention Each stereogenic carbon may be of the R or S configuration Although specific compounds may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned as part of the invention. Racemic mixtures are also encompassed within the scope of this invention

Detailed Description of the Invention Compounds disclosed herein may be prepared by the following reaction sequences as depicted m Schemes I or II below

Scheme 1

The compounds of Formula IX can be prepared according to Scheme 1.

Thus, clarithromycin of Formula II can be desmethylated with one or more reagent to give a compound of Formula III, which can further be demethylated to give a compound of Formula IV The compound of Formula IV can be reacted with compound

of Formula X'(CH2) _n X' (wherein, X' can be a leaving group, such as a halogen, and n is as defined earlier) to give a compound of Formula V. The compound of Formula V can be oximated to form a compound of Formula VI. The compound of Formula VI can be converted to a compound of Formula VII by Beckmann rearrangement, which in turn can be reduced using suitable reducing agent to give a compound of Formula VIII. The compound of Formula VIII can be N-methylated to give a compound of Formula IX.

Clarithromycin of Formula II can be desmethylated to give a compound of Formula III with one or more desmethylating agents, for example, sodium acetate trihydrate in iodine, N-iodo-succinimide iodine in acetic acid, diisopropylazodicarboxylate or mixture(s) thereof in the presence of one or more solvents, for example, methanol, dioxane, water, ethanol, 1-propanol, 2-propanol or mixture(s) thereof.

Compound of Formula III can be demethyated with sodium metal/iodine to give a compound of Formula IV in presence of one or more dry solvents, for example methanol, ethanol, propanol or mixture(s) thereof. Compounds of Formula IV can be reacted with a compound of Formula X ' (CFk) _n X ' to give a compound of Formula V in one or more solvents, for example, toluene, xylene, dimethylformamide, acetonitrile, methanol, acetone, tetrahydrofUran or mixture(s) thereof, in the presence of one or more bases, for example, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulfate, diisopropyl ethylamine or mixture(s) thereof.

The oximation of compounds of Formula V with hydroxylamine hydrochloride to give compounds of Formula VI can be carried out in presence of one or more bases, for example, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, cesium carbonate, triethylamine, sodium hydride, pyridine, sodium acetate, sodium thiosulfate, diisopropyl ethylamine or mixture(s) thereof in presence of one or more organic solvents, for example, methanol, ethanol, propanol, isopropanol or mixture(s) thereof.

The reaction of compounds of Formula VI to give compounds of Formula VTi can be carried out with oxime activating agents, for example, tosyl chloride, methanesulfonyl chloride, p-bromosulfonyl chloride in presence of one or more bases, for example, pyridine, triethylamine, diisopropylethylamine, tributylamine, 4-(N-dimethylamino)pyridine or

mixtures) thereof in one or more dry solvents, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixture(s) thereof.

The reduction of compounds of Formula VII to give compounds of Formula VIII can be carried out using various reducing agents, for example, platinum oxide, sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride or mixture(s) thereof optionally in presence of an acid for example acetic acid.

The compounds of Formula VHI can be iV-methylated to give compounds of Formula DC with one or more methylating reagent, for example, paraformaldehyde, formic acid, formaldehyde and mixture(s) thereof in one or more solvents, for example, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, or mixture{s) thereof.

The compounds of Formula XIII can be prepared following Scheme 2.

Thus, azithromycin of Formula X can be desmethylated with one or more reagent to give a compound of Formula XI, which can further be demethylated to give a compound of Formula XII. The compound of Formula XII can be reacted with a compound of Formula X'(CH ₂ ) _π X' (wherein, X' can be a leaving group, such as a halogen, and n is as defined earlier) to give a compound of Formula XIII.

Azithromycin of Formula X can be desmethylated to give a compound of Formula XI with one or more desmethylating agents, for example, sodium acetate trihydrate in iodine, N-iodo-succinimide iodine in acetic acid, diisopropylazodicarboxylate or mixture(s) thereof in the presence of one or more solvents, for example, methanol, water, dioxane, ethanol, 1-propanol, 2-propanol or mixture(s) thereof.

Compound of Formula XI can be bisdemethyated with sodium metal/iodine to give a compound of Formula XII in presence of one or more dry solvents, for example methanol, ethanol, propanol, or mixture(s) thereof.

Compounds of Formula XII can be reacted with one or more reagent of Formula X'(CH ₂ ) _n X' to give a compound of Formula XIII in one or more solvents, for example, acetonitrile, toluene, xylene, dimethylformamide, methanol, acetone, tetrahydrofuran or mixture(s) thereof, in the presence of one or more bases, for example, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulfate, diisopropyl ethylamine or mixture(s) thereof.

Other compounds of the invention can be similarly prepared starting from suitable starting compounds, such as those disclosed in international publication numbers WO 05030786, WO 06080954, WO 06129257, WO 06046112, WO 06013409, WO 06035301 and U.S. Patent No. 6,753,318

Experimental Procedures Synthetic Procedure of Scheme 1

Example 1: Synthesis of 5-O-f3'-N-bis-demetøyl-3'-N-pmolidin-l-yr)-6-O- methyl-9- deoxo-9a-aza-9a-methyl-9a-homoervthromvcm A (Compound No. 4) Stepl : Synthesis of 5-O-(3'-N-demethyl-3'-N-methyl)-6-O-methyl erythromycin A

Sodium acetate trihydrate (568.2 mmol) was added into the solution of clarithromycin (66.84 mmol) in methanol (320 mL), distilled water (80 mL) and dioxane (800 mL) at about 47 ^° C and iodine (137.7 mmol) was added after 10 minutes at the same temperature. The pH of the reaction mixture was maintained between 8-9 using 2 N sodium hydroxide and was stirred at 47 ^° C for about 10 hours. The reaction mixture was cooled to room temperature (~25 C) and was poured in aqueous ammonium hydroxide (-25%) and extracted with methylene chloride. The combined organic layer was washed with aqueous ammonium hydroxide (-25%), then with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give solid, which was crystallized in acetone-ammonium hydroxide (25% in water) to yield the title compound.

Yield: 90%

ESI-MS (m/z): 734 (M ⁺ +l)

Step 2: Synthesis of 5-O-(3'-N-bis-demethyl)-6-O-methyl erythromycin A

The pieces of sodium metal (16.35 mmol) were dissolved into the solution of degassed dry methanol (150 mL) at room temperature (-25 ⁰ C) and cooled to 0-5 C. To it, compound obtained from step 1 above (2.72 mmol) was dissolved and then iodine (13.62 mmol) was added and stirred at 5 ^° C for about 5 hours. This reaction mixture was poured in aqueous ammonium hydroxide (~25%) and sodium thio sulphate, extracted with methylene chloride. The combined organic layer was washed with aqueous ammonium hydroxide (~25%), then with brine and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give solid. The starting material was recovered by crystallizing it in acetone-ammonium hydroxide (-25%). The mother liquor was concentrated to solid and was purified by column chromatography using hexane-acetone- triethylamine as eluents to give the title compound

Yield: 16%

ESI-MS (m/z): 720.01 (M ⁺ +1)

Step 3: Synthesis of 5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-0-methyl erythromycin A

The solution of compound obtained from step 2 above (0.27 mmol), 1,4- dibromobutane (2.98 mmol) and sodium bicarbonate (1.08 mmol) in toluene (3.0 mL) was heated at about 110 ^° C for about 50 hours. The reaction mixture was cooled to about 25 C, filtered and washed with toluene. The mother liquor was concentrated under reduced pressure. The crude compound was dissolved in methylene chloride and washed with water, dried over anhydrous sodium sulphate, filtered and concentrated to give the solid. This was purified by column chromatography using hexane-acetone as eluents to give the title compound.

Yield: 57% ESI-MS (m/z): 774 (M ⁺ +l)

The following compounds were prepared using similar procedure as mentioned above:

5-O-(3 '-N-bis-demethyl-3 '-N-aziridin-1 -yl)-6-O-methyl erythromycin A ESI-MS (m/z): 747 (M ⁺ +!) 5-O-(3 '-N-bis-demethyl-3 '-N-azetidin-1 -yl)-6-O-methyl erythromycin A

ESI-MS (m/z): 760 (M ⁺ +l)

5-O-(3'-N-bis-demethyl-3'-N-piperidin-l-yl)-6-O-methyl erythromycin A ESI-MS (m/z): 788 (M ⁺ -K)

Step 4: Synthesis of 5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yI)-6-0-methyl- erythromycin A 9(E)-Oxime

I) A mixture of compound obtained from step 3 above (9.67 mmol), hydroxylamine hydrochloride (72.58 mmol) and potassium carbonate (38.7 mmol) in methanol (40 tnL) was refluxed for about 24 hours. This reaction mixture contained both E and Z isomers. This was cooled and evaporated. The crude solid was taken in dichloromethane and stirred for about 2 hours and filtered. The precipitate obtained contained major amount of the Z-isomer and E-isomer was in mother liquor. The mother liquor was evaporated and the crude solid obtained was stirred in dichloromethane, which was filtered. This solid was purified by column chromatography using hexane-acetone- triethylamine as eluents to give the pure E-isomer. Yield: 38%.

II): The above-obtained precipitate (majority of the Z-isomer) was dissolved in ethyl acetate, washed with the aqueous solution of sodium carbonate (pH~8.5 to 9). The organic layer was dried over sodium sulphate, filtered and concentrated to get the solid, which further was crystallized from nitromethane to get the Z-isomer of the title compound.

Yield: 5.2%

ESI-MS (m/z): 789 (M ⁺ +l)

Step 5: Synthesis of 5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yI)-6-0- methyl-9- deoxo-9a-aza-9,9a-an hydro homoerythromycin A 9a,ll-iminoether (Compound no. 1)

To a solution of the compound obtained from step 4 above (2.58 mmol) in dry dichloromethane (20 mL), tosyl chloride (2.58 mmol) was added in portions at 0 to 5 C and after 10 minutes, pyridine (2.58 mmol) was added over a period of about 2 minutes. The reaction mixture was stirred at 0 to 5 ^° C for about 6 hours. The reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulphate,

filtered and concentrated to get solid. The solid obtained was purified by column chromatography using hexane-acetone-triethylamine as eluents, to give the title compound.

Yield: 77% ESI-MS (m/z): 771(M ⁺ +1)

The following compound can be prepared by following the same procedure

5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl-9-d eoxo-9a-aza-9,9a-anhydro homoerythromycin A 9a,l 1-iminoether (Compound no. 2)

ESI-MS (m/z): 757.56 (M ⁺ +l) Step 6: Synthesis of 5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-0-methyl-9- deoxo-9a-aza-9a-homoerythromycra A (Compound no. 3)

The solution of compound obtained from step 5 above (0.389 mol) in platinum oxide (10% w/w) (0.030 g) and acetic acid (5 niL) was stirred at 0 to 5 ^° C and then at 25 ^° C for about 20 hours. The reaction mixture was filtered through the celite bed washed with 50% aqueous acetic acid, methanol and ethyl acetate. The mother liquor was concentrated completely and compound was taken in dichloroniethane, washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to get solid. The solid obtained was purified by column chromatography using hexane-acetone-triethylamine as eluents, to give the title compound.

Yield: 63%

ESI-MS (m/z): 775 (M ⁺ +l)

Step 7 : Synthesis of 5-O-(3 '-N-bis-demethyl-3 '-N-py rrolidin-1 -y l)-6-O-methyl-9- deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (Compound no. 4) The solution of compound obtained from step 6 above (0.08 mmol), paraformaldehyde (0.16 mmol) and formic acid (0.24 mmol) in chloroform (2 niL) was refluxed for about 45 minutes.

The reaction mixture was cooled and solvent was evaporated completely. The solid was dissolved in dichloromethane, washed with aqueous sodium bicarbonate, dried

over anhydrous sodium sulphate, filtered and concentrated to get solid. The solid thus obtained was purified by flash chromatography using hexane-acetone-triethylamine as eluents, to give the title compound.

Yield: 95% ESI-MS (m/z): 789 (M ⁺ +l)

Synthetic Procedure of Scheme 2

Example 2: Synthesis of S-Q-β'-N-bis-demethyl-S'-N-pyrrolidin-l-ylVg-deoxo-ga-aza- 9a-methyl-9a-homoervthromvcin A (Compound no. 5)

Step 1: Synthesis of 3 ^f -N-desmethyl azithromycin To the solution of azithromycin (33.37 mmol) in methanol (160 mL), distilled water (40 mL) sodium acetate trihydrate (166.8 mmol) was added at about 47 C and after 10 minutes iodine (33.7 mmol) was added at the same temperature. The pH of the reaction mixture was maintained between 8-9 using 2N NaOH and was stirred at about 47 ⁰ C for about 10 hours. Reaction mixture was cooled to room temperature (-25 C) and was poured in aqueous ammonium hydroxide (-25%), extracted with methylene chloride. The combined organic layer was washed with aqueous ammonium hydroxide (-25%), then with brine and dried over sodium sulfate, filtered and concentrated under reduced pressure to give solid, which was crystallized in acetone- ammonium hydroxide (25% in water) to yield the title compound. Yield: 77.5%

ESI-MS (m/z): 721.53 (M ⁺ +l)

Step 2: Synthesis of 3'-N,N-di-desmethyl azithromycin

Dry methanol (150 mL) was degassed using nitrogen gas over 30 minutes. To this, pieces of sodium metal (41.60 mmol) were dissolved at room temperature. It was cooled to 0-5 ^° C and compound obtained from step 1 above (2.77 mmol) was dissolved into it. Iodine (41.60 mmol) was added and stirred at 5 ^° C for about 5 hours. Reaction mixture was poured in aqueous ammonium hydroxide (~25%) and sodium thiosulphate and extracted twice with methylene chloride. The combined organic layer was washed with aqueous ammonium hydroxide (-25%), then with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give solid. The starting material was recovered by

crystallizing it in acetone-ammonium hydroxide (-25%). The mother liquor was concentrated and was purified by column chromatography using hexane-acetone- triethylamine as eluents to give of the title compound.

Yield: 15% ESI-MS (m/z): 735 (M ⁺ H-I)

Step 3: Synthesis of 5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-9-deoxo-9a-aza- 9a- methyl-9a-homoerythromycin A (Compound no. 5)

3'-N,N-di-desmethyl azithromycin (138.6 mmol) was dissolved in acetonitrile (5 mL) and then sodium bicarbonate (9.64 mol) was added into it at room temperature (~ 25° C). To this reaction mixture, 1,4-dibromobutane (9.25 mol) was added and the reaction mixture was further stirred for about 10 hours at about 35° C, This reaction mixture was filtered and concentrated under reduced pressure to give the title compound.

Yield: 65%

ESI-MS (m/z): 775.63 (M ⁺ H-I) The following compound was prepared using similar procedure as mentioned above

5 -O-(3 ' -N-bis-demethyl-3 ' -N-azetidin- 1 -yl)-9-deoxo -9a-aza-9a-methyl-9 a- homoerythro-mycin A (Compound no. 6)

ESI-MS (m/z): 761.82 (M ⁺ +l) 5-O-(3'-N-bis-demethyl-3'-N-ρiρeridin-l-yl)-9-deoxo-9a-aza -9a-methyl-9a- homoerythro- mycin A (Compound no. 7)

ESI-MS (m/z): 790 (M ⁺ H-I) Example 3 Pharmacological activity

Compounds disclosed herein displayed antibacterial activity in vitro especially against strains that are resistant to macrolides either due to efflux (mef strains) or ribosomal modification (erm) strains. These compounds are useful in treating community acquired pneumonia, upper strains 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 CO ₂ incubation (5% CO ₂ ) 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 (1.5 x 10 ⁸ CFU/mL). The cultures were diluted 10 fold in saline to obtain inoculum sizes of approximately 1-2 x 10 ⁷ organisms/ml.

Preparation of new chemical entities (NCEs) concentration

1 mg/ml concentration of stock solution of NCEs was prepared in dimethyl- sulfoxide/distilled water/solvent given in National Committee for Clinical Laboratory Standards (NCCLS) manual. Serial two-fold dilutions of the NCEs and standard antibiotics were prepared as per NCCLS manual. The concentration of stock solution was decided as per the requirement.

Preparation of Agar Plates

2 ml of respective NCE or standard antibiotic 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 any standard antibiotic or NCE for each set were prepared as controls. One MHA and MHA with 5% sheep blood

plate without any standard antibiotic or NCE 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 {i.e. , Denley's multipoint replicator). The spots were allowed to dry and the plates were incubated for about 18-24 hours at 37 ⁰ C. Fastidious cultures were incubated at 37 ⁰ C in a CO ₂ incubator. The results were noted comparing with the control plates.

Endpoint definition

The concentration of NCE or standard antibiotic 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 NCE's. Precautions & Quality Control Measures

Quality Control Strains

Staphylococcus aureus ATCC 29213

Enterococcus faecalis ATCC 29212

Eschericia coli ATCC 25922 Pseudomonas aeruginosa ATCC 27853

All 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.

The compounds described and claimed had the following MIC values:

References:

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).

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 have shown good activity against microbial strains, for example, Staphylococcus aureus. Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, and Enterococcusfaecalis. a) The compounds described herein exhibited MIC values against sensitive Streptococcus pneumoniae 6303 in the range of between about 2 μg/mL to about 16 μg/mL. b) The compounds described herein exhibited MIC values against Haemophilus influenzae 38 in the range of between about 0.03 μg/mL to about

16 μg/mL. c) The compounds described herein exhibited MIC values against sensitive Streptococcus pyogenes 19615 in the range of between about 2 μg/mL to about 16 μg/mL. d.) Additionally, the compound Sdescribed herein exhibited MIC values against Staphylococcus pneumoniae 99619, Haemophilus influenzae 99297, and Staphylococcus aureus in the range of between about 4 μg/mL to about 8 μg/mL.