Wednesday, 15 October 2014

MACROLIDE DERIVATIVES AS ANTIBACTERIAL AGENTS

Balasaheb kakade marked as one of the inventor in this patent application below find attached.for more details pls email us info@rxnchem.com

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, Moraxella spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Enterobactericeae or any combination thereof Also provided, are processes for preparing 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 ah, Am. J. Physiol, 1984, 247:688; Omura, S et ai, J. Med. Chem., 1987, 30: 1942-43). 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. Macro lides 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 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 macroJide 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 compounds having the structure of Formula I, 

Formula I
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof, wherein:
the dashed bond between C-IO and C-I l, depicted by ( — ), represents an optional bond n can be an integer from 2 to 7,
Ri and R2 can be independently hydrogen, hydroxy, OC(=Z')VR7, SO2R7, Formula A or Ri and R2 together can form oxo or thio group;


Formula A
wherein Z' can be oxygen or sulfur; V can be -W(CH2V ; k can be an integer of from 0 to 6; W can be no atom, -NR8- or oxygen; R8 can be hydrogen or alkyl; alkylene chain of -W(CH2)k- can be optionally substituted with alkyl, hydroxy or alkoxy; R7 can be alkyl, aryl, heterocyclyl or heteroaryl; R9 is hydroxyl, alkoxy, -O(CH2)iWRb,
-0C(0)N(Rs)(CH2)dWRb, .NHCO(CH2)hWRb or -OC(O) (CH2XWRb (wherein Rbis heterocyclyl or heteroaryl; W is as defined earlier; 1 is an integer 0-5, d, h can be integer 2-6 and t can be an integer 1-6) and R10 is hydrogen or hydroxy protecting group;
R' is Rio, wherein R10 is defined previously;
R3 can be hydrogen, alkyl or -(CH2)r-U; r can be an integer of from 1 to 4; U can be optionally substituted alkenyl or alkynyl;
T can be hydrogen, halogen, cyano or alkyl;
X and Y can be independently selected from hydrogen, -OR10, -KRi 1R12 or taken together with the carbon atoms to which they are attached to form C(=Z'), C=NRo, C=NC(O)R13
wherein Rn and R12 can be hydrogen, alkyl or taken together with the nitrogen atom to which they are attached form a 3-10 membered heterocycloalkyl ring system; R13 can be alkyl, alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl; Ri4 is hydrogen; alkyl; cycloalkyl; arylalkyl; alkylheterocyclyl, alkyl- heteroaryl, R1S is hydrogen or alkyl or Ri4 and R1S taken together with the carbon atom to which they are attached form a C3-Ci2 cycloalkyl ring system; R1^ is selected from a group consisting of hydrogen, alkyl or cycloalkyl;
R4 can be hydrogen, alkyl, -OR10, or -NH(CH2)qRi7, wherein Rn is aryl or heteroaryl and q can be an integer between 0 to 4;
R5 can be hydrogen, hydroxyl, -OCORi7, -ORi0 wherein Rn and Ri0 is defined previously;
R6 can be alkyl, alkenyl or alkynyl;
further, R4 and R5, together with their carbon atoms to which they are attached (Cn and C]2), can form a group represented by Formula B


Formula B
Ri 8 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 R19 is no atom when A is O and M-R20 when A is N wherein M can be alkenyl, -G(CH2)mJ, -CR7Ry, -NR7- or -SO2 - {[wherein m can be an integer from 2 to 6, G can be no atom, -CO, -CS, -SO2 or -NR7, J can be no atom or -N((R7)(CH2)P- (wherein p can be an integer of from 1 to 4, R7 and R9 can be
independently hydrogen or alkyl)]} ; R2o can be no atom, hydrogen, aryl or heterocyclyl or heteroaryl;
X and R4 can, together with the carbon atoms at the 9- and 11 -position of the
erythronolide skeleton, form a group represented by Formula C


Formula C
where R2i can be alkyl, hydroxyl, alkoxy, phenoxy or aryl; p is defined previously;
X and R3 can, together with the carbon atoms to which they are attached (C9 and C6), form a ring represented by Formula D


Formula D
where R21 is defined previously;
or, R3 and R4 can, together with the carbon atoms at the 6- and 11 -position of the erythronolide skeleton, form a group represented by Formula E


L can be -CH2-C(R22)=C(R23)-CH2-, -CH2-CH(R22)-C(R23)=CH-, -CH2-CH(R24)-
CH(R25)-CH2-, -CH2-C(R33)(R24)-CH2-CH2- or , HH= , wherein R22 and R23 are hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R24 and R25 are independently selected from R22, -ORi0, SO2R71 NHC(O)R22, NHC(O)N(R3)(R22), NHSO2R7 or NR11Ri3; R23 and R24 taken together with the carbon atom to which they are attached are selected from C=O,C(OR6)2, or C=N-O-R22; Q is -0-, -N(R22)-, -OC(O)-CH(R22)-, 0-C(O)-N(R22)^-O-C(O)-O-, N(R22)-N=N-; C(R22)=N-O- or CH(R33)-NH-O-.
In another aspect, provided herein are compounds selected from
5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-O-methyl erythromycin A (Compound 1) 5-O-(3'-N-bis-demethyl-3'-N-aziridin-l-yl)-6-O-methyl erythromycin A (Compound 2) 5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A (Compound 3) 5-O-(3 '-N-bis-demethyl-3 '-N-piperidin-l-yl)-6-0-methyl erythromycin A (Compound 4)
5-O-(3 '-N-bis-demethyl-S'-N-pyrrolidin- 1 -yl)-3-O-decladinosyl-6-O-methyl-3-hydroxy erythromycin A (Compound 5)
5-O~(3 '-N-bis-demethyl-3 '-N-azetidin-l-yl)-6-O-methyl-3-hydroxy erythromycin A (Compound 6)
5-0- {(3 '-N-bis-demethyl-S'-N-pyrrolidin- 1 -yl)-2'-O-benzoyl} -3-0-decladinosyl-ό-O-methyl-3-hydroxy erythromycin A (Compound 7)
5-O-[(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-2'-O-acetyl]-3-O-decladinosyl-6-O-methyl-3 -hydroxy erythromycin A (Compound 8)
5-O-{(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-2'-O-benzoyl}-l l,12-dideoxy-3-O-decla-dinosyl-6-O-methyl-3-hydroxy-12,l l-(dioxycarbonyl)erythromycin A (Compound 9)
5-0- {(3 ' -N-bis-demethyl-3 ' -N-pyrrolidin-l-yl)-2' -O-benzoylj -11 -deoxy-3-0-decladinosyl-6-O-methyl-3-hydroxy-10,ll-anhydro erythromycin A (Compound 10)
5-O-{(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-2'-O-benzoyl}-l l-deoxy-3-O-decladinosyl-6-O-methyl-3-oxo-10,l l-anhydro erythromycin A (Compound 11)
S-O-CS'-N-bis-demethyl-S'-N-pyrrolidin-l-ylJ-l l-deoxy-S-O-decladmosyl-ό-O-meihyl-3-oxo-10,l l-anhydro-12-O-(imidazole-l-carbonyl)erythromycin A (Compound 12) 5-0- {(3'-N-bis-demethylO'-N-py.τolidin- 1 -yl)-2'-0-benzoyl} -11 , 12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo- 12, 11 -[oxycarbonyl-(4-(4-(pyridin-3'yl)-imidazol- 1 -yl)-butylimino)] erythromycin A (Compound 13)
S-O-CS'-N-bis-demethylO'-N-pyrroUdin-l-y^-l l.π-dideoxy-B-O-decladinosyl-δ-O-methyl-3-oxo-12,l 1 -[oxycarbonyl-(4-(4-(pyridin-3-yl)-imidazol-l-yl)-butylimino)] erythromycin A (Compound 14)
S-O-tS'-N-bis-demethyl-S'-N-pyrrolidin-l-y^-l U^-dideoxy-S-O-decladinosyl-β-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(2-amino-pyrimidin-5-yl)-imidazol-l-yl)-butylimino)] erythromycin A (Compound 15)
5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-O-methyl-3-hydroxy erythromycin A 9(E)-(O-benzyloxy)oxime (Compound 16)
5-O-(3'-N-bis-demethyl-3'-N-ρyrrolidin-l-yl)-6-O-methyl erythromycin A 9(E)-0xime (Compound 17)
5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-O-methyl erythromycin A 9(Z)-0xime (Compound 18)
5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A 9-oxime (Compound 19)
5-O-(3'-N-bis-dememyl-3'-N-azetidm-l-yl)-6-O-methyl erythromycin A 9-(O-methoxy) oxime (Compound 20)
S-O-fS'-N-bis-demethyl^'-N-azetidin-l-yO-S-O-decladinosyl-ό-O-methyl-S-hydroxy-erythromycin A 9-(O-methoxy)oxime (Compound 21)
In yet another aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds of Formula 1 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 Formula 1 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, catheter infection, foreign body, prosthesis infections or peptic ulcer disease.
In another embodiment, the bacteria) 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 are 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, cholin, 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.
Definitions
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 -NRn-, wherein R01 can be hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl, - C(=O)ORχ, SOmR^ or -C(K))NRxR7T. 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(C i-6alkyl), -CH=N-NH(Ci-6alkyl), 
alkyl)- Ci-6 alkyl, arylthio, thiol, alkylthio, aryloxy, nitro, amino sulfonyl, aminocarbonylamino, 
-
{wherein Rx and R1 are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or carboxy}, nitro or -SOmR^ (wherein m is an integer from 0-2 and R1/, is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclyl alkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, -NRxR7T, 

-OC(=O)NRλR]r,-NHC(=O)NRλRτ, hydroxy, alkoxy, halogen, CF3, cyano, and -SOmR^; or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NRo- (wherein Ra, Rx, R7n m and Rψ 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, -NRxR7T, -C(=0)NRλRπ, -0-C(^O)NRxR7T, hydroxy, alkoxy, halogen, CF3, cyano, and -SOmRψ (wherein Rx, Rτ, m and Rψ 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., -CH2CH2CH2 and -CH(CH3)CH2) 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^, -NHQ=O)Rx, -NRxR1, -Ct=O)NRxR1, -NHQ=O)NRxR7T, -C(=O)heteroaryl, C(=0)heterocyclyl, -0-Cf=O)NRxR7T, nitro, -S(O)mRx (wherein Rx, R^, m and R^ are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, -COOR^, -NRxR,., -Q=0)NRλRπ, -OQ=O)NRxR,-, -NHC(=0)NRλRπ, hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)mRψ (wherein Rx, Rπ, 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 -NRa (wherein Rα 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, -Q=O)OR,/,, halogen, CF3, cyano, -NRλRπ, -S(O)01R^, -Q=O)NRxRx, -0C(=0)NRλRπ, -CONH-, -C=O or -C=NOH (wherein Rx, R7T, m and R1/, 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 -NRo- (wherein R01 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, -NHC(O)Rx, -NRxRx, -Q=O)NRxR1, -NHC (O)NRxRx, -O-C(=O)NRχRT)
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 SOnJR^ (wherein Rx, R1, 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, -CF3, cyano, -NRxR7n, - C(=O)NRXRT, -0-C(=0)NRxRπ and -SOmR^ (wherein Rλ, Rff, m and R^ are as defined earlier). Groups, such as ethenyl or vinyl (CH=CH2), 1 -propylene or allyl (-
bicyclo[2.2.1]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(O)Rx, -NRλRΛ -Cf=O)NRxRx, -NHC(=0)NRλRir,-0C(=0)NRλRir (wherein Rx and Rx are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR,/, (wherein R^ is the same as defined earlier), arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, alkoxyamino, nitro, -S(O)mR^ (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 alky], alkenyl, alkynyl, carboxy, -COOR,/, (wherein Rψ is the same as defined earlier), hydroxy, alkoxy, halogen, -CF3, cyano, -NRxR1, -Q=O)NRxR7T, -OQ=O)NRxR7T (wherein Rx and R1 are the same as defined earlier) and -S(O)mR^ (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 -NR0T(wherein R01 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, amino sulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, 
-Ct=O)NRxR7T, -O-C(=O)NRχRx or -SOmR^ (wherein Rx, Rπ, 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, CF3, -NRxR1T, 
-NHC(K))NRxR7T, -Q=O)NRxR7T, cyano or -SOmR^ (wherein Rx, Rτ, m 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, -NHQ=O)Rx, -NRxRff, -NHQO)NRxR,.
(wherein Rx and Rx are the same as defined earlier), -S(O)mR^ (wherein Rψ 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, CF3, -NRχR,τ, -C(^O)NRxR71, -NHCt=O)NRxR7,-, -Ct=O)NRxR7n(wherein Rx and R1 are the same as defined earlier), cyano, and -S(O)111R^ (wherein R^ 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, cycloalkeny], acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NRxR7T, -NHC(=O)NRxR,r, -NHC(=O)Rχ, -C(=0)NRλRτ, -0-C(=0)NRλRπ, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or SOmRψ (wherein Rx, Rτ, m and R^ 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, CF3, -NRxR7T, -Ct=O)NRxR1, -NHC(-0)NRλRTO-
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, cycloalkyi, alkoxy, acyl, aryloxy, CF3, cyano, nitro, -CHO, OCF3, -SCF3, COOR^, NHC(O)Rx, -NRxRx, -Q=O)NRxR1n -NHC(=O)NRλRx, -0-Q=O)NRxRx, -SOmR^, carboxy, heterocyclyl, heteroaryl, hetero eye IyI alkyl, hetero aryl alkyl or amino carbonyl amino, mercapto, haloalkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, thioalkyl, -CONHRx, -OCORx, -CORx, -NHSO2R^Or -SO2NHRx (wherein Rx, Rx, m and R1/, are the same as defined earlier). Aryl groups optionally may be fused with a cycloalkyi group, wherein the cycloalkyi 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, naphthylniethyl 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(=0)0H.
The term "heteroaryl," unless otherwise specified, refers to an aromatic monocyclic or polycyclic (fused, spiro or bridged) ring system containing 1-8
hetero atom(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, -OCF3, -CF3, -SCF3, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NRxR7T, CH=NOH, -(CH2)WC(^O)R7, {wherein w is an integer from 0-4 and R,, is hydrogen, hydroxy, ORx, NRλRπ, -NHORω or -NHOH}, -Cf=O)NRxR1 -NHC(=O)NRλRΛ -SO01R*, -0-C(=0)NRλRπ, -0-Q=O)Rx, or -O- Q=O)ORx (wherein m, R^, Rx and Rτ are as defined earlier and Rω is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl alkyl). Unless otherwise constrained by the definition, the substiruents 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, 6H-pyrido-[l,2-α]pyrimidinyl, tetrahydropyranyl, thiazolidinyl, thiazolyl, thienyl, pyridazinyl, carbazolyl, isobenzofuranyl, thianthrene, triazinyl, furanyl, benzofuranyl, tetrazolyl, quinazolinyl, benzoxazinonyl, benzothiazinonyl and the like.
The term "cyclo alkenyl" 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 -NR5Rg, wherein R5 and R6 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 "halo alkyl" 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 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., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, optionally substituted aryl, alkoxy, alkaryl, cyano, nitro, oxo, -CHO, -OCF3, -CF3, -SCF3, carboxy, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, -0-Q=O)Rx, -0-C(^O)ORx, -C(=0)NRxRπ, SOmR^, -O-C(O)NRxR^, -NHC(=0)NRxRπ, -NRXRT, mercapto, haloalkyl, thioalkyl, -COOR^, -COONHRx, -CORx, -NHSO2Rx or SO2NHRx (wherein m, R^, Rx and Kπ 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-benzodioxanyl, 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 -C(=0)R# wherein R^ is selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaryl alkyl or heterocyclylalkyl. "Alkylcarbonyl" refers to -Q=O)R^, wherein R^ is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaryl alkyl or heterocyclylalkyl.
"Alkylcarboxy" refers to O C(K))R^, wherein R^ is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaryl alkyl or heterocyclylalkyl.
"Amine," unless otherwise specified, refers to -NH2. "Substituted amino" unless otherwise specified, refers to a group -N(Rk)2 wherein each Rk is independently selected from the group hydrogen provided that both R11 groups are not hydrogen (defined as "amino"), alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryJ, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, S(O)7nR,/, (wherein m and R^ are the same as defined above), -C(=Rv)NRλRy (wherein Rv is O or S & R\ and Ry are the same as defined earlier) or NΗC(=Rv)NRyRχ (wherein Rv, Ry 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, -COOR1/, (wherein R^ is the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, -C(=Rv)NRχRy (wherein Rv is the same as defined earlier), -0(C=0)NRλRy, -OC(=Rv)NRλRy (wherein Rx, Ry and Rv are the same as defined earlier), -S(O)1nR^ (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, CF3, cyano, -C(=T)NRχRτ, -0(C=O)NRxR1(wherein Rx, Rπ and T are the same as defined earlier) and -OQ=T)NRxR70 -SOmR^ (wherein m and R1/, 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", 3rd 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, hi 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-liydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic, 2-hydroxyethanesulfonic acid and the like.
The phrase "pharmaceutically acceptable carriers" is intended to include nontoxic, 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, atropisomers and comformational 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. 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 nonsuperimposable 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 σ 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 disclosed herein may be prepared by the following reaction sequences as depicted in Schemes I, II or III below.
Scheme 1


The compounds of Formula V 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 FII, which can further be bisdemethylated to give a compound of Formula IV. The compound of Formula IV can be reacted with, suitable reagent of Formula X(CF^)nX (wherein, X can be halogen and n can be 2-7) to give a compound of Formula V.
Clarithromycin of Formula II to give a compound of Formula III can be desmethylated 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 solvent(s), for example, methanol, dioxane, ethanol, 1-propanol, 2-propanol or mixture(s) thereof,
Compound of Formula HT can be bisdemethyated with sodium metal/iodine to give a compound of Formula IV in presence of one or more solvent(s), for example methanol, ethanol, propanol or mixture(s) thereof.
Compound of Formula IV can be reacted with one or more reagent of Formula X(CH2)nX to give compounds of Formula V in one or more solvent(s), for example, toluene, xylene, dimethylformamide, acetonitrile, methanol, acetone, tetrahydrofuran or mixture(s) thereof, in the presence of one or more inorganic or organic base(s), for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulfate, diisopropyl ethylamine or mixtures thereof.
XU


FormulaXI 
Compounds of Formula XlV can be prepared following scheme 2.
Thus, compounds of Formula V can be hydrolyzed to give compounds of Formula VI. The compounds of Formula VI can be protected with suitable hydroxyl protecting group of Formula (R)2θ to give compounds of Formula VII (wherein RpT is COPh or COMe) Compounds of Formula VII can be reacted with triphosgene to form compounds of Formula VIlI, which can be further reacted to give compounds of Formula IX. The compounds of Formula IX can be oxidized to give compounds of Formula X, which can then be reacted with N,N'-carbonyldiimidazole to give compounds of Formula XI The compounds of Formula XI can be reacted with suitable amine R2O-MNH2 of Formula XII (wherein M and R20 is as defined earlier) to give compounds of Formula XIII. The compounds of Formula XIII can be deprotected to give compounds of Formula XIV.
Compounds of Formula V can be hydrolyzed to give compounds of Formula VI in the presence of an acid, for example, hydrochloric acid, sulfuric acid or dichloroacetic acid.
Compounds of Formula VI can be hydroxyl protected to give compounds of Formula VII by reacting with Formula (Rpr)2O to form compounds of Formula VII in one or more solvent(s), for example, dichloromethane, acetone, dichloroethane, chloroform, carbon tetrachloride, acetonitrile or mixture(s) thereof, in the presence of one or more base(s), for example, triethylamine, potassium carbonate, diisopropylethylamine, pyridine, tributylamine, sodium carbonate, sodium bicarbonate or mixture(s) thereof.
Compounds of Formula VII can be reacted with triphosgene to form compounds of Formula VIII in one or more solvent(s), for example, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or mixture(s) thereof, in the presence of one or more organic base(s), for example, pyridine, triethylamine, diisopropyl ethylamine, tributylamine or mixture(s) thereof.
Compounds of Formula VIII can be reacted to give compounds of Formula IX with one or more organic base(s), for example, tetramethyl guanidine, trimethyl amine or mixtures thereof, in one or more solvents), for example, Λ^N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide or mixtures thereof.
Compounds of Formula IX can be oxidized to give compounds of Formula X with one or more oxidizing agent(s), for example, Dess-Martin periodinane, N-chlorosuccinimide, pyridinium chlorochromate, Swem Oxidation reagent (oxalyl chloride and dimethylsulfoxide), Pfitzner-Moffatt Oxidation reagent (dicyclohexylcarbodiimide and dimethylsulfoxide), Jones Oxidation reagent (chromic acid, aqueous sulfuric acid and acetone), pyridinium dichromate, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or mixtures thereof, N-Chlorosuccinamide can be used in combination with dimethyl sulfide and l-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride can be used in combination with dimethylsulfoxide, in the presence of one or more solvents, for example, dichloromethane, dichloroethane, chloroform, dimethylsulfoxide, carbon tetrachloride or mixture(s) thereof.
Compounds of Formula X can be reacted with N,N'-carbonyldiimidazole to form compounds of Formula XI in one or more solvent(s), for example, dimethyl formamide, acetonitrile, tetrahydrofuran or mixture(s) thereof, in the presence of one or more base(s), for example, sodium hydride, sodium hydrogen, carbonate, sodium acetate, sodium thiosulfate, potassium carbonate or cesium carbonate.
Compounds of Formula XI can be reacted with one or more amine of Formula R2O-M-NH2 to give compounds of Formula XIII in one or more solvent(s), for example, acetonitrile, dimethylformamide, water or combinations thereof.
Compounds of Formula XIII can be deprotected to form compounds of Formula XIV in one or more solvent(s), for example, methanol, ethanol, propanol, isopropanol or mixture(s) thereof.
Scheme 3
Compounds of Formula XV, XVI and XVIII can be prepared following scheme 3. Compound of Formula V can be reacted through three pathways.
Path A: Compounds of Formula V can be oximated with benzyloxyhydroxylamine hydrochloride to give compounds of Formula XV.
Path B: Compounds of Formula V can be oximated with hydroxylamine hydrochloride to give an E+Z mixture of compounds of Formula XVI, which can be further purified to its E and Z isomers.
Path C: Compound of Formula V can be oximated with methoxylamine hydrochloride to give a compound of Formula XVII, which can be hydrolyzed to give compounds of Formula XVIIL
The oximation of compound of Formula V with benzyloxyhydroxylamine hydrochloride to give a compound of Formula XV (path A) can be carried out in presence of one or more base(s), for example, triethylamine, potassium carbonate, sodium hydrogen carbonate, cesium carbonate, sodium hydride, pyridine, sodium acetate, sodium thiosulfate, diisopropyl ethylamine or mixture(s) thereof in presence of one or more organic solvent(s), for example, methanol, etlianol, propanol, isopropanol or mixture(s) thereof.
The oximation of compound of Formula V with hydroxylamine hydrochloride
(Path B) to give an E+Z mixture of compound of Formula XVI can be carried out under similar conditions as conversion of compound of Formula V into compound of Formula XV. The compound of Formula XVI can further be purified to give E and Z isomers.
The oximation of compound of Formula V with methoxylamine hydrochloride (Path C) to give a compound of Formula XVII can be carried out under similar conditions as conversion of compound of Formula V into compound of Formula XV. The compound of Formula XVII can further be hydrolyzed to give a compound of Formula XVIII in presence of an acid, for example, hydrochloric acid, sulfuric acid or dichloroacetic acid.
In the above schemes, where specific reagents, for example, bases, acids oxidizing agents, solvents, etc., are disclosed, 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 are:
5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-O-methyl erythromycin A (Compound 1) 5 -O-(3 ' -N-bis-demethyl-3 '-N-aziridin- 1 -yl)-6-O-methyl erythromycin A (Compound 2) 5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A (Compound 3) 5 -O-(3 '-N-bis-demethyl-3 '-N-piperidin-l-yl)-6-O-methyl erythromycin A (Compound 4)
5-O-(3 '-N-bis-demethyl-3 '-N-pyrrolidin- 1 -yl)-3-O-decladinosyl-6-O-methyl-3-hydroxy erythromycin A (Compound 5)
5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl-3-hydroxy erythromycin A (Compound 6)
5-0-{(3'-N-bis-demethyl-3'-N-ρyrrolidin-l-yl)-2'-0-benzoyl}-3-0-decladmosyl-6-0-methyl-3-hydroxy erythromycin A (Compound 7)
5 -O-[ (3 ' -N-bis-demethyl-3 ' -N-azetidin- 1 -yl)-2 ' -O-acetyl] -3 -O-decladinosyl-6-O-methyl-3 -hydroxy erythromycin A (Compound 8)
5-O-{(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-2'-O-benzoyl}-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-hydroxy-12,l l-(dioxycarbonyl)erythromycin A (Compound 9)
5-0- {(3 '-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-2'-O-benzoyl} - 1 l-deoxy-3-O-decladinosyl-6-O-methyl-3-hydroxy-10,l l-anhydro erythromycin A (Compound 10) 5-0- {(3 '-N-bis-demethyl-3'-N-pyrrolidin-l -yl)-2'-O-benzoyl} - 1 l-deoxy-3-0-decladinosyl-6-O-methyl-3-oxo-10,l l-anhydro erythromycin A (Compound 11)
5-O-(3 ' -N-bis-demethyl-3 '-N-pyrrolidin- 1 -yl)- 11 -deoxy-S-O-decladinosyl-δ-O-methyl-S-oxo-lO^l-anhydro-^-O-^midazole-l-carbony^erythromycin A (Compound 12)
5-0- {(3 ' -N-bis-demethy]-3 '-N-pyrrolidin- 1 -yl)-2'-0-benzoyl} -11,12-dideoxy-3-O-decladinosyl-ό-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(pyridin-3-yl)-imidazol-l-yl)-butylimino)] erythromycin A (Compound 13) 5-O-(3'-N-bis-demethyl-3'-N"pyrrolidin-l-yl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(pyridin-3-yl)-imidazol-l-yl)-butylimino)] erythromycin A (Compound 14)
5 -O-(3 ' -N-bis-demethyl-3 ' -N-pyrrolidin- 1 -yl)- 11 , 12-dideoxy-3 -O-decladinosyl-6-0-methyl-3-oxo- 12, 1 l-[oxycarbonyl-(4-(4-(2-amino-pyrimidin-5-yl)-imidazol-l -yl)-butylimino)] erythromycin A (Compound 15)
5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin- 1 -yl)-6-O-methyl-3 -hydroxy erythromycin A 9(E)-(O-benzyloxy)oxime (Compound 16)
5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-O-methyl erythromycin A 9(E)-0xime (Compound 17)
5-O-(3'-N-bis-demethyl-3 '-N-pyrrolidin- 1 -yl)~6-O-methyl erythromycin A 9(Z)-0xime (Compound 18)
5-O-(3 '-N-bis-demethyl-3 '-N-azetidin-l-yl)-6-O-methyl erythromycin A 9-oxime (Compound 19)
5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A 9-(O-methoxy) oxime (Compound 20)
5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-3-O-decladinosyl-6-O-methyl-3-hydroxy-erythromycin A 9-(O-methoxy)oxime (Compound 21)
or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs, metabolites or polymorphs thereof.
The compounds disclosed 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 disclosed 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,
polyvinylpyrrolidinone, 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, dimethyl formamide, 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 mixture(s) thereof.
Injectable preparations, for example, sterile injections, 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 mixture(s) 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 pharmaceutically 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.
Experimental Procedures
Synthetic Procedure of Scheme 1
Example 1
Synthesis of 5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-O-methyl erythromycin A
Stepl : Synthesis of 5-O-(3'-N-demethyl-3'-N-methylV6-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 0C and iodine (137.7 mmol) was added after 10 mins at the same temperature. The pH of the reaction mixture was maintained between 8-9 using 2 N NaOH and was stirred at 47 0C for about 10 hours.
Reaction mixture was cooled to room temperature (-25 0C) and was poured in -25% aqueous ammonium hydroxide and extracted with methylene chloride. The combined organic layer was washed with -25% aqueous ammonium hydroxide, followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give crude solid, which was crystallized from acetone-aqueous ammonium hydroxide to yield 3'-N-desmethyl clarithromycin,
yield: 90%
ESI-MS (m/z): 734 (M++!)
Step 2: Synthesis of 5-O-C3'-N-bis-demethylV6-O-methyl erythromycin A
The pieces of sodium metal (16.35 mmol) were dissolved into degassed dry methanol (150 ml) at room temperature(~25 0C) and cooled to 0-50C. 3'-N-desmethyl clarithromycin (2.72 mmol) was dissolved in it and then iodine (13.62 mmol) was added and stirred at about 5 0C for about 5 hours. This reaction mixture was poured in 25% aqueous ammonium hydroxide and sodium thiosulphate, extracted with methylene chloride. The combined organic layer was washed with - 25% aqueous ammonium hydroxide ammonium hydroxide, then with brine and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give crude solid. The starting material was recovered by crystallizing it from acetone-25% aqueous ammonium hydroxide. The mother liquor was concentrated to crude solid and was purified by column chromatography using hexane-acetone-triethylamine as eluent to give the title compound
Yield: 16%
ESI-MS (m/z): 720.01 (M++l)
Step 3: Synthesis of 5-O-r3'-N-bis-demethyl-3'-N-pyrrolidin-l-vn-ό-O-methyl erythromycin A
The solution of 3'-N,N-di-desmethyl clarithromycin (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 0C for about 50 hours.
Reaction mixture was cooled to room temperature (-25 0C), filtered through sintered funnel and washed with toluene. The mother liquor was concentrated to minimum volume at about 500C 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 eluent to give the title compound.
Yield: 57%
ESI-MS (m/z): 774 (M++!)
Following compounds were prepared using similar procedure as mentioned above 5-O-(3'-N-bis-demethyl-3'-N-aziridin-l-yl)-6-O-methyl erythromycin A
ESI-MS (m/z): 747 (M++l)
5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A
ESI-MS (m/z): 760 (M++l)
5 -O- (3 ' -N-bis-demethyl-3 ' -N-pip eridin- 1 -yl)-6-Omethyl erythromycin A
ESI-MS (m/z): 788 (M++l) Synthetic Procedure of Scheme 2
Example 2
Synthesis of 5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-π,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(pyridin-3-yl)-imidazol-l-yl)-butylimino)]erythromycin A
Step 1 : Synthesis of 5-CK3 '-N-bis-demethyl-3 '-N-pyrrolidin-1 -vD-3-Q-decladinosyl-6-O-methyl-3 -hydroxy erythromycin A
The solution of 5-O-(3'-N-bis-demethyl-3'-N-pyrτolidm-l-yl)-6-O-methyl erythromycin A (0.103 mmol) in IN HCl (2 ml) was stirred at room temperature for 25 min. After the solution became clear, ethyl acetate was added and this reaction mixture was basified to pH 7.5-8. The aqueous layer was separated, extracted with ethyl acetate, washed with water and then brine and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane-acetone as eluent, to yield the title compound.
Yield: 66%
ESI-MS (m/z): 616 (M++l)
Following compound was prepared using similar procedure as mentioned above
5-O-(3 '-N-bis-demethyl-3'-N-azetidin- 1 -yl)-6-O-methyl-3-hydroxy erythromycin A
ESI-MS (m/z): 602 (M++l)
Step 2: Synthesis of 5-O-{r3'-N-bis-demethyl-3'-N-pyrrolidin-l-ylV2'-O-beEzoyll-3-O-decladinosyl -6-O-methyl-3-hydroxy erythromycin A
Benzoic anhydride (8.1 1 mmol) and triethylamine (16.2 mmol) were added to a solution of compound 5-O-(3'-N-bis-demethyl-3'-N-pyrrolidm-l-yl)-3-O-decladinosyl-6-O-methyl-3-hydroxy erythromycin A (3.25 mmol) in dichloromethane (20 ml) and the reaction mixture was stirred for about 40 hours. The solution was then basified and stirred for another 15 min. The organic layer was separated, washed with water and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane-acetone as eluent to give the title compound.
Yield: 86.8%
ESI-MS (m/z): 720 (M++l)
Following compound was prepared using the similar procedure as mentioned above
S-O-ttS'-N-bis-demethyl-S'-N-azetidin-l-y^-l'-O-acetyη-S-O-decladinosyl-ό-O-metbyl-3 -hydroxy erythromycin A
ESI-MS (m/z)t 644.64 (M++!)
Step 3: Synthesis of 5-Q-((3'-N-bis-demethyl-3τ-N-τ)yrrolidin-l-vn-2'-O-benzovU-11 ,12-dideoxy-3-O-decladinosyl-6-Q-methyl-3-hydroxy-12.11 -(dioxycarbonyl)
erythromycin A
Triphosgene (3.366 mmol) was added to an ice-cooled solution of compound 5-O-{(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-2'-O-benzoyl}-3-O-decladinosyl-6-O-methyl-3-hydroxy erythromycin A (2.8 mmol) in dichloromethane (20 ml) and the reaction mixture was stirred for about 10 min. Pyridine (33.666 mmol) was added dropwise and the temperature was maintained to about 5 0C. The reaction mixture was further stirred for about 4 hours at 0 0C, water was added to the reaction mixture, allowed to stir for 1 hour and diluted with dichloromethane. Organic layer was separated, washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane-acetone as eluent to give the title compound.
Yield: 82.18 %
ESI-MS (m/z): 746.69 (M++l)
Step 4: Synthesis of 5-O-ff3'-N4)is-demethyl-31-N-pwolidm-l-ylV2'-O-benzoyli-ll-deoxy-3-O-decladinosv1-6-O-methyl-3-hydroxy-10J l-anhydro erythromycin A
1,1,3,3-Tetramethyl guanidine (5.01 mmol) was added to a solution of compound 5-O-{(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-2'-O-benzoyl}-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-hydroxy-12,ll-(dioxycarbonyl) erythromycin A (2.28 mmol) in N,N-dimethylformamide (10 ml) and the reaction mixture was heated at 70-80 0C for about 6 hours. The reaction mixture was then cooled and poured onto ice-cold water. The separated precipitate was filtered out, dissolved in dichloromethane, washed with water followed by brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound.
Yield: 95.01%
ESI-MS (m/z): 702.66 (M++l)
Step 5: Synthesis of S-O-IG'-N-bis-demethyl-S'-N-pyrrolidin-l-ylW-O-benzovU-1 l-deoxy-3-O-decladinosyl-6-O-methyl-3-oxo-10,l 1-anhydro erythromycin A
Dess-Martin periodinane (3.1 mmol) was added portion wise to a solution of compound 5-O- {(3 '-N-bis-demethyl-3 '-N-pyrrolidin-l-yl)-2'-O-benzoyl} -11 -deoxy-3-O-decladinosyl-6~O-methyl-3 -hydroxy- 10,11-anhydro erythromycin A (2.065 mmol) in dichloromethane (15 ml) over a period of 15-25 min at 25 0C and this reaction mixture was stirred for about 40 min. It was then cooled to 15-200C and to it saturated aqueous solution of potassium carbonate was added slowly to a pH 7.5 to 8 and stirred for about 1 hour. To this, 10% aqueous sodium thiosulphate solution was added and again stirred for about 1 hour. This solution was filtered and dichloromethane layer was separated, washed with water followed by brine, concentrated under reduced pressure. The crude product was then purified by column chromatography using hexane-acetone as eluents to give the title compound. Yield: 55.3%
ESI-MS {m/z): 700.67 (M++l)
Step 6: Synthesis of 5-Q-r3)-N-bis-demethyl-3'-N-pyrrolidm-l-yl)-l l-deoxy-3-O-decladinosyl-6-O-methyl-3-oxo-10J l-anhydro-12-O-(irnidazole-l-carbonyl)
erythromycin A
Carbonyl diimidazole (3.43 mmol) was added to a solution of compound 5 -O- {(3 '-N-bis-demethyl-3 '-N-pyrrolidin-l -yl)-2'-0-benzoyl}-l l-deoxy-3-0-decladinosyl-6-0-methyl-3-oxo-10,l 1-anhydro erythromycin A (1.143 mmol) in dimethylformamide (6 ml) and tetrahydrofuran (3 ml) at about -150C and reaction mixture was stirred for about 10 min. To it, sodium hydride (3.43 mmol) was added in portions at -15 0C and again stirred for 10 min. The reaction mixture was poured onto ice-cold water, extracted from ethyl acetate, combined organic layer was washed with water and then with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Yield: 99.5%
ESI-MS (m/z): 794.76 (M++l)
Step 7: Synthesis of 5-O-{β'-N-bis-demethyl-3'-N-pyrrolidin-l-ylV2'-O-benzoyl}-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-f4-(4-fpyridin-3-yl)-imidazol-l-yl)-butylimino)1 erythromycin A
The solution of compound 5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-ll-deoxy-3-0-decIadinosyl-6-O-niethyl- 3 -oxo- 10 , 11 -anhydro- 12-O-(imidazole- 1 -carbonyl) erythromycin A (0.39 mmol) and 4-(3-pyridin-3-yl-pγrτol-l-yl)-butylamine (1.17 mmol) in acetonitrile - water mixture (4.5ml+0.5ml) was heated at 60-65 0C for about 30 hours. The acetonitrile- water mixture was evaporated under reduced pressure and the resulting residue was purified by column chromatography using acetone-hexane as eluents to give the title compound.
Yield: 54 %
ESI-MS (m/z): 942.88 (M++l)
Step 8: Synthesis of S-O^'-N-bis-demethyl-S'-N-pyrrolidm-l-ylVll.^-dideoxy-S-Q-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-('pyridin-3-ylVimidazol-l-yl)-butylimino)] erythromycin A
A solution 5-O-{(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-2'-O-benzoyl}-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-l 2, 1 l-[oxycarbonyl-(4-(4-(pyridin-3-yl)-imidazol-l-yl)-butylimino)] erythromycin A (0.191 mmol) in methanol (3 ml) was refluxed for about 16 hours. The solvent was removed under reduced pressure. The resulting residue was purified over column chromatography using methanol-dichloromethane as eluent to yield the title compound.
Yield: 50%.
ESI-MS (m/z): 838.70 (M++l)
Following compound was prepared following the similar procedure.
S-O-tS'-N-bis-demethyl-S'-N-pyrrolidin-l-yO-l ^^-dideoxy-S-O-decladinosyl-δ-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(2-amino-pyrimidin-5-yl)-imidazol-l-yl)-butylimino)] erythromycin A.
Yield: 50 %
ESI-MS (m/z): 855 (M++l)
Synthetic Procedure of Scheme 3
Example 3
Synthesis of 5-O-(3 '-N-bis-demethyl-3 '-N-pyrrolidin-l-yl)-6-0-methyl-3-hydroxy erythromycin A 9(E)-(0-benzyloxy)oxime
Path A: The solution of 5-O-(3'-N-bis-demethyl-3'-N-ρyrrolidin-l-yl)-6-O-methyl erythromycin A (0.645 rnmol), 0-benzyloxyhydroxylamine hydrochloride (3.87 mmol) and triethylamine (1.935 mmol) in methanol (5 ml) was refluxed for about 12 hours. Reaction mixture was cooled and concentrated to get solid, which was purified by column chromatography using hexane-acetone as eluent to give the title compound.
Yield: 52 %
ESl-MS (m/z): 721 (M++l)
Example 4
Synthesis of 5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-0-methyl erythromycin A 9(E)-Oxime and
5-0-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-0-methyl erythromycin A 9(Z)-Oxime Path B:
Step I: 5-0- f3'-N-bis-demethyl-3'-N-ρyrrolidin-l-ylV6-O-me1hyl erythromycin A 9(EV Oxime
A mixture of 5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-O-methyl erythromycin A (9.67 mmol), hydroxylamine hydrochloride (72.58 mmol) and potassium carbonate (38.7 mmol) in methanol (40 ml) was refluxed for about 12 hours. This reaction mixture contained both E and Z isomers. This was cooled and diluted with dichloromethane. The precipitate obtained contained major amount of the Z-isomer and E-isomer was in mother liqour. 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 as eluents to give the pure E-isomer.
Yield: 38%.
Step 2: 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): 789.75 (M++l)
Example 5
Synthesis of 5-O-(3 '-N-bis-demethyl-3 '-N-azetidin-l-yl^-O-decladinosyl-ό-O-methyl-3-hydroxy erythromycin A 9-(0-methoxy)oxime
Path C:
Step 1 : Synthesis of 5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-Q-methyl erythromycin A 9-(O-methoxy)oxime
The solution of 5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A (0.658 mmol), methoxylamine hydrochloride (3.95 mmol) and potassium carbonate (1.97 mmol) in methanol (4 ml) as reflux ed for about 16 hours. Reaction mixture was cooled and the excess solvent was evaporated to get the solid. The solid was dissolved in ethyl acetate, washed with the aqueous solution of sodium bicarbonate (pH -8.5 to 9). The organic layer was dried over sodium sulphate, filtered and concentrated to get the solid which further was purified by column chromatography using acetone-hexane as eluents to give the compound 5-O-(3'-N-bis-dememyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A 9(E+Z)-0xime.
Yield: 25 %
ESI-MS (m/z): 790 (M++l)
Following compound was prepared following the similar procedure as above
5 -O-(3 '-N-bis-demethyl-3 '-N-pyrrolidin- 1 -yl>ό-O-methγlerythromycin A 9(E)-(O-methoxy) oxime.
Step 2 : Synthesis of 5-Q-r3'-N-bis-demethyl-3T-N-azetidin-l-ylV3-O-decladinosyl-6-O-methyl- 3 -hydroxy erythromycin A 9-(O-methoxy)oxime
The solution of 5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A 9-(O-methoxy)oxime (0.234 mmol) in IN HCl (5 ml) was stirred at room temperature for about 25 min. After the solution became clear, ethyl acetate was added and this reaction mixture was basified with aqueous solution of potassium carbonate to a pH 7.5-8. The aqueous layer was separated, extracted with ethyl acetate, washed with water and then brine and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane-acetone as eluent, to yield the title compound.
Yield: 47.38%
ESI-MS (m/z): 631.61 (M++!)
Example 6. 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 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 370C for about 18-24 hours. Fastidious cultures were incubated CO2 incubation (5% CO2) at 37 0C 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 108 CFU/ml). The cultures were diluted 10 fold in saline to obtain inoculum sizes of approximately 1-2 x 107organisms/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 0C. Fastidious cultures were incubated at 37 0C in a CO2 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:
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 have shown good activity against microbial strains, for example, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, and Enterococcus faecalis .
a) The compounds described herein exhibited MIC values against
Staphylococcus aureus in the range of between about 0.125 μg/mL to
about 32 μg/mL.
b) The compounds described herein exhibited MIC values against sensitive Streptococcus pneumoniae in the range of between about 0.03 μg/mL to about 64 μg/mL.
c) The compounds described herein exhibited MIC values against
erythromycin resistant Streptococcus pneumoniae in the range of between about 16 μg/mL to about 64 μg/mL.
d) The compounds described herein exhibited MIC values against
Haemophilus influenzae in the range of between about 0.06 μg/mL to about 64 μg/mL.
e) The compounds described herein exhibited MIC values against sensitive
Streptococcus pyogenes in the range of between about 0.06 μg/mL to about 16 μg/mL.
f) The compounds described herein exhibited MIC values against
erythromycin resistant Streptococcus pyogenes in the range of between about 0.25 μg/mL to about 64 μg/mL.
g) The compounds described herein exhibited MIC values against methicillin resistant Staphylococcus aureus s in the range of between about 16 μg/mL to about 64 μg/mL.
h) The compounds described herein exhibited MIC values against sensitive Enterococci species in the range of between about 0.125 μg/mL to about
32 μg/mL.
i) The compounds described herein exhibited MIC values against resistant Enterococci species in the range of between about 16 μg/mL to about 64 μg/mL.

Ranbaxy Patent application

Pub. No.:  WO/2008/099368  International Application No.:  PCT/IB2008/050568
Publication Date:21.08.2008International Filing Date:15.02.2008
IPC:
C07H 17/08 (2006.01), A61K 31/7028 (2006.01), A61P 31/04 (2006.01)
Applicants:RANBAXY LABORATORIES LIMITED [IN/IN]; Plot No. 90, Sector - 32, Gurgaon, Haryana 122001 (IN) (For All Designated States Except US).
CHAKRABARTI, Anjan [IN/IN]; (IN) (For US Only).
SURASE, Yogesh, Baban [IN/IN]; (IN) (For US Only).
KAKADE, Balasaheb [IN/IN]; (IN) (For US Only).
DAS, Biswajit [IN/IN]; (IN) (For US Only).
UPADHYAY, Dilip J. [IN/IN]; (IN) (For US Only)
Inventors:CHAKRABARTI, Anjan; (IN).
SURASE, Yogesh, Baban; (IN).
KAKADE, Balasaheb; (IN).
DAS, Biswajit; (IN).
UPADHYAY, Dilip J.; (IN)
Common
Representative:
RANBAXY LABORATORIES LIMITED; c/o George E. Heibel, 600 College Road East, Suite 2100, Princeton, NJ 08540 (US)
Priority Data:
319/DEL/2007 15.02.2007 IN
Title(EN) MACROLIDE DERIVATIVES AS ANTIBACTERIAL AGENTS
(FR) DÉRIVÉS DE MACROLIDES UTILISÉS COMME AGENTS ANTIBACTÉRIENS
Abstract:front page image
(EN)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, Moraxella spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Enterobactericeae or any combination thereof. Also provided, are processes for preparing compounds disclosed herein, pharmaceutical compositions containing compounds disclosed herein, and methods of treating bacterial infections.
(FR)La présente invention concerne des dérivés de macrolides pouvant être utilisés comme agents antibactériens. Les composés de l'invention peuvent être utilisés pour traiter ou prévenir des affections causées ou induites par des bactéries Gram positives, Gram négatives ou anaérobies, et agissent notamment contre Staphylococcus, Streptococcus, Enterococcus, Haemophilus, Moraxella spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium,Bacteroides, Corynebacterium, Bacillus, Enterobactericeae ou une combinaison quelconque de celles-ci. L'invention concerne également des procédés de préparation des composés susmentionnés, des compositions pharmaceutiques renfermant ces composés et des méthodes de traitement d'infections bactériennes.