ANTIBACTERIAL AGENTS
FIELD OF THE INVENTION
The present invention provides acylide derivatives, which can be used as antibacterial agents. Compounds disclosed herein can be used for the treatment or prevention of a condition caused by or contributed to by gram positive, gram negative or anaerobic bacteria, more particularly against bacterium such as Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae. Process for the preparation of disclosed compounds are provided, as well as pharmaceutical compositions containing the disclosed compounds, and method of treating bacterial infections.
BACKGROUND OF THE INVENTION
The first generation macrolides erythromycin A and the 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, 247: 688, 1984; Omura, S et al, J. Med. Chem, 30: 1943, 1987). Various erythromycin A derivatives have been prepared to overcome the acid instability and other problems associated with it.
Roxithromycin, clarithromycin and azithromycin have been developed to address the limitation of erythromycin A. Both clarithromycin and azithromycin have proved to be important drugs in the treatment and prophylaxis of atypical Mycobacterial infectious in patients with HIV.
Macrolides have proved 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 the favorable safety profile, and 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.
WO 01/10878, 01/10879 and 01/10880 disclose novel erythromycin derivatives having potent antibacterial effects on erythromycin-resistant bacteria and Haemophilus influenzae.
WO 99/21870 discloses erythromycin A, 11,12-carbamate derivatives having antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin-resistant bacteria.
U.S. Patent No. 5,444,051 discloses novel erythromycin compounds, antibiotic composition and a method of combating bacteria infection in warm-blooded animals.
U.S. Patent No. 6,191,118 discloses erythromycin A derivatives having strong antibacterial activity against erythromycin-resistant bacteria.
U.S. Patent No. 5,631,354 discloses 5-O-desosaminylerythronolide derivatives possessing antibacterial activity.
U.S.Patent No. 6,020,521 discloses a class of macrolide compounds which are antagonists of luteinizing hormone-realising hormone (LHRH).
SUMMARY OF THE INVENTION
The present invention provides acylide 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, stereoisomers, prodrugs, 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.
Other object will be set forth in accompanying description which follows and in part will be apparent from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there are provided compounds having the structure of Formula I, as shown in the accompanied drawing, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs or polymorphs, wherein R1can be o hydrogen
o hydroxyl protecting group R2 and R3 can independently be selected from
o alkyl (with the provisio that R2 and R3 simultaneously are not methyl)
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocycle
o aralkyl
o (heterocycle)alkyl R4 can be
o alkyl
o alkenyl
o alkynyl R5 can be
o aryl
o heterocycle R can be
o no atom
o aryl
o heterocycle R' can be
o alkyl
o -(CH2)q-U-V wherein q can represent an integer 1 to 4 U can be
- alkenyl
- alkynyl V can be
- hydrogen
- aryl
- heterocycle W can be
o alkenyl
o -G(CH2)mJ - wherein m can represent an integer 2 to 6 and G can be
- no atom
- -CO
- -CS
- -S02
- -NR9 o -CR9R10 o -NR9-
o -S02 wherein R9 and R10 can be selected from
- hydrogen
- alkyl J can be
- no atom
-N(CH2)n- , wherein n can represent an integer 1 to 4, R9 can be hydrogen or
R9 alkyl
Y can be o -Q(CH2)k-, wherein k can represent an integer 1 to 6, Q can be
- no atom
- -NR9- wherein R9 represents hydrogen or alkyl
oxygen
one of the hydrogen atom of alkylene chain can be optionally replaced by
o alkyl
o hydroxy
o alkoxy Z can be
o oxygen
o sulphur
o NOR8 wherein R8 can be
- hydrogen
- alkyl
- aralkyl
In accordance with a second aspect, there is provided a method for treating or preventing a mammal suffering from a condition caused by or contributed to by gram positive, gram negative or anaerobic bacteria, comprising administering to said mammal, a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein.
The bacterial infection may be caused by bacterium such as Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae.
The said conditions may be, for example, community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or bone and joint infections, and other bacterial infections such as mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease.
In accordance with a third aspect, there is provided processes for the preparation of disclosed compounds.
As used herein the term "alkyl" refers to straight or branched saturated hydrocarbon having one to six carbon atom (s). One or more hydrogen atom (s) of the said alkyl can optionally be replaced by halogen, hydroxy, alkoxy, cycloalkyl, cycloalkoxy, -NHCOR9, -NHCOOR9, -OCOR9 or -COR9, wherein R9 is alkyl, aryl or heterocycle. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl and butyl, and the like.
As used herein the term "alkenyl or alkynyl" stands for unsaturated hydrocarbon having two to six carbon atoms. One or more hydrogen atom (s) of said alkenyl or alkynyl can be replaced by halogen, hydroxy, mercapto, alkoxy or thioalkyl. Examples of alkenyl and alkynyl include, but are not limited to, ethylene, propylene, ethynyl and propynyl, and the like.
As used herein the term "cycloalkyl" refers to saturated carbocyclic ring having three to seven carbon atoms. One or more hydrogen atom (s) of said cycloalkyl can be replaced by halogen, hydroxy, mercapto, alkoxy or thioalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl and cyclopentyl, and the like.
As used herein the term "halogen or halo" refers to fluorine, chlorine, bromine or iodine.
As used herein the term "hydroxyl-protecting group" includes, but are not limited to, acyl, aroyl, alkyl, aryl, butyldiphenylsilyl, methoxymethyl and methylthiomethyl, and the like.
As used herein the term "thio" refers to the group -SH.
As used herein the term "alkoxy" stands for a group O-R wherein R refers to alkyl or cycloalkyl. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, cyclopentoxy and the like.
As used herein the term "thioalkyl" refers to -SR wherein R refers to alkyl or cycloalkyl.
As used herein the term "haloalkyl" refers to alkyl of which one or more hydrogen (s) is/are replaced by halogen.
As used herein the term "aryl" stands for an aromatic radical having 6 to 14 carbon atoms. Examples of aryl include, but are not limited to, phenyl, napthyl, anthryl and biphenyl, and the like.
As used herein the term "aralkyl" stands for an aryl radical having 7 to 14 carbon atoms, which is bonded to an alkylene chain. Examples of aralkyl include, but are not limited to, benzyl, napthylmethyl, phenethyl and phenylpropyl, and the like.
As used herein the term "heterocycle" refers to non-aromatic or aromatic ring system having one or more heteroatom (s) such as nitrogen, sulphur or oxygen, the ring system includes mono, bi or tricyclic which is optionally attached via heteroatom. Examples of heterocycles include, but not limited to, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothieenyl, benzotriazolyl , 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, tetrahydropyranyl, thiazolidinyl, thiazolyl, thienyl, and the like.
As used herein the term "(heterocycle) alkyl" stands for heterocycle which is bonded to an alkylene chain. Examples of heterocycle alkyl include, but are not limited to, isothiazolidinyl ethyl, isothiazolyl propyl, pyrazinyl methyl, pyrazolinyl propyl and pyridyl butyl, and the like.
The said aryl and heterocycle may optionally be substituted with one or more substituent (s) independently selected from the group consisting of hydroxy, nitro, mercapto, cyano, alkyl,
haloalkyl, alkoxy, thioalkyl, optionally substituted aryl, optionally substituted heterocyclyl, -NR6R7, -CONR6R7, -COOR7, -CONHR7, -OCOR7, -COR7, -NHS02R7, and -S02NHR7, wherein R6 and R7 are independently selected from the group comprising of hydrogen and alkyl.
As used herein the term "polymorphs" includes all crystalline forms and amorphous forms for compounds described herein.
The term "pharmaceutically acceptable solvates" refers to solvates with waters (i.e hydrates) or pharmaceutically acceptable organic solvents. Such solvates are also encompassed within the scope of this invention.
The phrase "pharmaceutically acceptable salts" denotes salts of the free base, which
possess the desired pharmacological activity of the free base and which are neither biologically
nor otherwise undesirable. Suitable pharmaceutically acceptable salts may be prepared from an
inorganic or organic acid. Example of such inorganic acids include, but not limited to,
hydrochloric, hydrobromic, hydroiodic, nitrous (nitrile salt), nitric (nitrate salt), carbonic,
sulfuric, phosphoric acid and like. Appropriate organic acids include, but not limited to,
aliphatic, cycloaliphoric, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids,
such as, for example, formic, acetic, propionic, succenic, glycolie, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumeric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-
hydroxyethanesulfonic, sulfanilic, stearic, algenic, beta-hydroxybutyric,
cyclohexylaminosulfonic, galactaric and galacturonic acid and the like.
"The term pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
The compounds of present invention include stereoisomers. The term "stereoisomer" refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomer and comformational isomers. Geometric isomers may occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity. An enantiomer is a stereoisomer of a reference molecule that is the 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 conformational 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 a bonds, and are often rapidly interconverting at room temperature. Racemic mixtures are also encompassed within the scope of this invention.
The present invention also includes within its scope prodrugs of these agents. In general, such "prodrugs" will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "design of prodrugs", ed. H Bundgaard and, Elsevier, 1985.
DETAILED DESCRIPTION OF THE INVENTION
The compounds disclosed herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in Schemes I and II of the accompanied drawings. Scheme 1
The compound of Formula XII can be prepared according to Scheme I as shown in the accompanied drawings. Thus, clarithromycin of Formula II is hydrolyzed to give a compound of Formula III, which on protection with a reagent of Formula R^O or R!X (wherein X is halogen) gives a compound of Formula IV (wherein R1 is -COPh), which on desmethylation at 3'-N-dimethyl group gives a compound of Formula V, which on alkylation with a reagent of Formula R3CHO, R32CO or R3X gives a compound of Formula VI (wherein R3 is the same as defined earlier), which on reaction with a suitable reagent gives a compound of Formula VII, which on reaction with a suitable organic base gives a compound of Formula VE, which on acylation with a reagent of Formula R5YCOOH, (R5YCO)20, R5YCOX or R5YCOOR10 (wherein R10 is leaving group such as pivaloyl, p-toleuensulfonyl, isobutoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl) gives a compound of Formula IX (wherein Y and R5 are the same as defined earlier), which on reaction with N, N'-carbonyl diimidazole gives a compound of
Formula X, which on reaction with a compound of Formula R-W-NH2 gives a compound of Formula XI (wherein R and W are the same as defined earlier), which is finally deprotected to give a compound of Formula XII.
The hydrolysis of clarithromycin of Formula II to give a compound of Formula HI can be carried out in the presence of an inorganic or organic acid, for example, hydrochloric acid, sulphuric acid or dichloroacetic acid.
The hydroxyl protection of a compound of Formula HI to give a compound of Formula IV can be carried out in a suitable solvent, for example, dichloromethane, dichloroethane, chloroform or ethyl acetate.
The hydroxyl protection of a compound of Formula III to give a compound of Formula IV can be carried out in the presence of an organic base, for example, triethylamine, pyridine, tributylamine or 4-N-dimethylaminopyridine.
The desmethylation of a compound of Formula IV to give a compound of Formula V can be carried out in the presence of a suitable demethylating agent, for example, N-iodosuccinamide or diisopropyl azodicarboxylate.
The desmethylation of a compound of Formula IV can be carried out in a suitable solvent, for example, acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate or mixture thereof.
The quenching of desmethylation reaction can be carried out in the presence of a suitable quenching agent, for example, sodium bisulphite, sodium carbonate or mixture thereof.
The alkylation of a compound of Formula V to give a compound of Formula VI can be carried out in a suitable solvent, for example, dimethylformamide, acetonitrile or tetrahydrofuran.
The alkylation of a compound of Formula V to give a compound of Formula VI can be carried out in an inorganic or organic base, for example, sodium hydrogen carbonate, potassium carbonate, sodium hydride, pyridine, triethylamine or diisopropyl ethylamine.
The alkylation of a compound of Formula V can also be carried out with a reagent of Formula R3CHO with a reducing agent, for example, sodium cyanoborohydride, sodium borohydride or sodium triacetoxyborohydride in the presence of an organic acid, for example, acetic acid or dichloroacetic acid in a suitable solvent, for example, methanol, ethanol, propanol or isopropanol.
The reaction of a compound of Formula VI to give a compound of Formula VII can be carried out in the presence of suitable reagent, for example, triphosgene or ethylene dicarbonate.
The reaction of a compound of Formula VI to give a compound of Formula VII can be carried out in a suitable solvent, for example, chloroform, dichloromethane, carbon tetrachloride or dichloroethane.
The reaction of a compound of Formula VI can be carried out in the presence of an organic base, for example, triethylamine, pyridine, tributylamine or 4-N-dimethylaminopyridine.
The reaction of a compound of Formula VII to give a compound of Formula VIII can be carried out in a suitable solvent, for example, dimethylformamide, tetrahydrofuran or dimethylsulphoxide.
The reaction of a compound of Formula VII to give a compound of Formula VIII can be carried out in the presence of an organic base, for example, tetramethyl guanidine, pyridine or trimethylamine.
The reaction of a compound of Formula VIE to give a compound DC can be carried out in a suitable solvent, for example, dichloromethane, dichloroethane, acetone, ethyl acetate or tetrahydrofuran.
The reaction of a compound of Formula VHI to give a compound IX can be carried out in the presence of an inorganic or organic base, for example, sodium bicarbonate, potassium carbonate, triethylamine, pyridine, tributylamine or 4-N-dimethylaminopyridine.
The reaction of a compound of Formula VIE to give a compound DC can be carried out in the presence of an activating agent, for example, dicyclohexylcarbodiimide or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
The reaction of a compound of Formula DC with N, N'-carbonyl diimidazole to give a compound of Formula X can be carried out in a suitable solvent, for example, dimethylformamide, tetrahydrofuran or mixture thereof.
The reaction of a compound of Formula DC can be carried out in the presence of an inorganic base, for example, sodium hydrogen carbonate, potassium carbonate or sodium hydride.
The reaction of a compound of Formula X with a compound of Formula R-W-NH2 to give a compound of Formula XI can be carried out in a suitable solvent, for example, acetonitrile, water, dimethylformamide or mixture thereof.
The deprotection of a compound of Formula XI to give a compound of Formula XII can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol.
The compound of Formula XII can further be converted into its salt by following the conventional method well known in the prior art.
Scheme II
The compound of Formula XV can be prepared according to Scheme II as shown in the accompanied drawings. Thus, a compound of Formula X (from scheme I) is reacted with hydrazine hydrate to give a compound of Formula XIII, which on deprotection gives a compound of Formula XIV, which is finally reacted with a compound of Formula R (CH2)mCHO to give a compound of Formula XV (wherein R and m are the same as defined earlier).
The reaction of a compound of Formula X with hydrazine hydrate to give a compound of Formula XIII can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran or dimethylsulphoxide.
The deprotection of a compound of Formula XHI to give a compound of Formula XIV can be carried out in a solvent, for example, methanol, ethanol, propanol or isopropanol.
The reaction of a compound of Formula XIV with a compound of Formula R(CH2)mCHO to give a compound of Formula XV can be carried out in a solvent, for example, methanol, ethanol, propanol or isopropanol.
The reaction of a compound of Formula XIV to give a compound of Formula XV can be carried out in the presence of an organic acid, for example, acetic acid or dichloroacetic acid.
The reaction of a compound of Formula XIV to give a compound of Formula XV can be carried out in the presence of a reducing agent, for example, sodium borohydride , sodium cyanoborohydride or sodium triacetoxyborohydride.
The compound of Formula XV can further be converted into its salt by following the conventional method well known in the prior art.
In the above scheme, where the specific bases, activating agents, solvents, etc., are mentioned, it is to be understood that bases, activating agents, solvents, etc., known to those skilled in the art may be used. Similarly, the reaction temperature and duration may be adjusted according to the desired needs.
The compounds disclosed herein possess antibacterial activity against gram-positive, gram-negative and anaerobic bacteria. They are useful as antibacterial agents for the treatment of bacterial infections in human and animal. Compounds of the present invention useful for such purpose are listed below (also shown in Table I):
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-O-methyl-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-imino]erythromycin A (Compound No. 1),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,l l-[oxycarbonyl-((4-imidazol-l-yl)-butyl)-imino]erythromycin A (Compound No. 2),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-O-methyl-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-imino] erythromycin A (Compound No. 3),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3*-N-desmethyl-3'-N-ethyl)-6-O-methyl-12,11 -[oxycarbonyl-((4-(3H)-imidazo(4,5-b)-pyridin-3-yl)-butyl)-imino] erythromycin A (Compound No. 4),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-
6-O-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yi)-butyl)-imino] erythromycin A
(Compound No. 5),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-
6-O-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-imino]erythromycin A
(Compound No. 6),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,l l-[oxycarbonyl-(prop-2-en-yl)-imino]erythromycin A (Compound No. 7),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-imidazol-l-yl)-butyl)-imino]erythromycin A (Compound No. 8),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-imidazol-l-yl)-butyl)-imino]erythromycin A (Compound No. 9),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3"-N-desmethyl-3*-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-benzimidazol-l-yl)-butyl)-imino]erythromycin A (Compound No. 10),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-benzimidazol-l-yl)-butyl)-imino] erythromycin A (Compound No. 11),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(3H)-imidazol-[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 12),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(lH)-imidazol-[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 13),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-
methyl-12,11 -[oxycarbonyl-((4-pyrrolo-[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 14),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-indol-l-yl)-butyl)-imino]erythromycin A (Compound No. 15),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-
methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 16),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-( 1 H)-imidazol-[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 17),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4- indol- l-yl)-butyl)-imino]erythromycin A (Compound No. 18),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4- benzimidazol- l-yl)-butyl)-imino]erythromycin A (Compound No. 19),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-
methyl-12,11 -[oxycarbonyl-((4-pyrrolo-[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 20),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(3H)-imidazol-[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 21),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-
methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 22),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyHCN'-methyl-N -pyridin-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 23),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pvridylacetyl)-5-0-(3,-N-desmethyl-3,-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((N1-methyl-N -pyridin-2-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 24),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((N1-methyl-N -pyridin-3-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 25),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((N'-methyl-N -quinolin-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 26),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3,-N-desmethyl-3,-N-allyl)-6-0-
methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 27),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(l H)imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino] erythromycin A (Compound No. 28),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 29),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(2-methyl)-benzoimidazo-1 -yl)-butyl)-imino] erythromycin A (Compound No. 30),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3,-N-allyl)-6-0-
methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 31),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3*-N-desmethyl-3,-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-pyridin-2-yl)-butyl)-imino]erythromycin A(Compound No. 32),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-pyridin-4-yl)-butyl)-imino]erythromycin A(Compound No. 33),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-benzoimidazo-l-yl)-butyl)-imino]erythromycin A (Compound No. 34),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3,-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A(Compound No. 35),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-benzotriazol-l-yl)-butyl)-imino]erythromycin A(Compound No. 36),
-11,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A(Compound No. 37),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3,-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A(Compound No. 38),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3"-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A(Compound No. 39),
-11,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A(Compound No. 40),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-propargyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A(Compound No. 41),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(3H)imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A(Compound No. 42),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3,-N-desmethyl-3*-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((9-(4-amino-butyl)9H-purin-6-yl)-imino]erythromycin A(Compound No. 43),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzoimidazo-1 -yl)-butyl)-imino] erythromycin A(Compound
No. 44),
-11,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A(Compound No. 45),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A(Compound No. 46),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A(Compound No. 47),
-11,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-benzotriazol-l-yl)-butyl)-imino]erythromycin A(Compound No.
48),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A(Compound No. 49),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A(Compound No. 50),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-propargyl)-6-O-methyl-12,11 -[oxycarbonyl-((4-benzoimidazo-1 -yl)-butyl)-imino]erythromycin A(Compound No. 51),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-benzotriazol-l-yl)-butyl)-imino]erythromycin A(Compound No.
52),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(l H)imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino] erythromycin A(Compound No. 53),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-benzotriazol-l-yl)-butyl)-imino]erythromycin A(Compound No.
54),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-benzotriazol-l-yl)-butyl)-imino]erythromycin A(Compound No.
55),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-propargyl)-6-O-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A(Compound No. 56)
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3,-N-allyl)-6-0-
methyl-12,11 -[oxycarbonyl-((4-(4-furan-2-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 57)
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3,-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-thiophen-2-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A (Compound No. 58)
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3,-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-( (9-(3-hydrazino-propyl)-9-H-purin-6-yl-4-amino)]erythromycin A (Compound No. 59).
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs or polymorphs.
(TABLE REMOVED)
In another aspect, there is provided pharmaceutical composition, which may be administered to an animal for treatment orally, topically, rectally, internasally, or by parenteral route. The pharmaceutical compositions of disclosed compounds comprise a pharmaceutically effective amount of a compound described herein formulated together with one or more pharmaceutically acceptable carriers.
Solid form preparation for oral administration includes capsules, tablet, pills, powder, granules, cachets and suppository. For solid form preparation, the active compound is mixed with at least one inert, pharmaceutically acceptable excipients or carrier, for example, sodium citrate, dicalcium phosphate and/or a filler or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia; disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate; absorption acceletors ,for example, quaternary ammonium compounds; wetting agents ,for example, cetyl alcohol, glycerol mono stearate; adsorbants ,for example, Kaolin; lubricants ,for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium luaryl sulphate and mixture thereof. In the case of capsules, tablets, pills, the dosage form may also comprise bufferring agents.
The solid preparation of tablets, capsules, pills and granules can be prepared with coating and shells, for example, enteric coating and other coatings well known in the pharmaceutical formulating art.
Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. For liquid form preparation, the active compound is mixed with water or other solvent, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castorand sesame oil), glycerol, and fatty acid esters of sorbitan and mixture thereof. Besides inert diluents, the oral composition can also include adjuants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents and perfuming agents.
Injectable preparations, for example, sterile injections, aqueous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride.
Dosage form for tropical or transdermal administration of a compound of the present invention includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powder and solution are also contemplated as being within the scope of this invention.
The pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be packaged preparation, the package containing discrete capsules, powders, in vials or ampoules, and ointments capsule, sachet, tablet, gel, cream itself or it can be the appropriate number of any of these packaged forms.
The quantity of active compound in unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and potency of the active ingredient.
In therapeutic use as agents for treating bacterial infections the compounds utilizing in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily. The dosages, however, may be varied depending upon the requirements of the patients and the compound being employed.
Determination of the proper dosage for a particular situation is within the smaller dosages, which are less than the optimum dose. Small increments until the optimum effect under the daily dosage may be divided and administered in portion during the day if desired.
Examples set forth below demonstrate the general synthetic procedure for the preparation of representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not constrain the scope of the present invention as defined by the claims.
EXPERIMENTAL DETAILS
General Procedure
Scheme I
Preparation of compound of Formula III
To a solution of hydrochloric acid was added clarithromycin of Formula II (25g, 33.4 mmol). The reaction mixture was neutralized with solid sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. Organic layer was washed with water, brine, and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to give the desired product. The crude product was crystallized by using ethyl acetate- hexane mixture.
Preparation of compound of Formula IV
To a solution of compound of Formula in (I equiv) in dry dichloromethane was added benzoic anhydride (2.5 equiv), triethylamine (6 equiv) and stirred at ambient temperature. Reaction was quenched by aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane, washed successively with water, brine, and dried over anhydrous sodium sulphate and then the solvent was removed under reduced pressure to give a crude product. The crude product was crystallized by using ethyl acetate - hexane mixture.
Preparation of compound of Formula V
To a solution of compound of Formula IV (1 equiv) in dry acetonitrile: dichloromethane (2:1) was added N-iodosuccinimide (2 equiv). The reaction mixture was stirred with sodiumbisulphite solution followed by stirring with sodium carbonate solution. Dichloromethane was evaporated under reduced pressure. The aqueous matter was extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous sodiumsulphate and then the
solvent was removed under reduced pressure to yield a crude product. The crude product was purified by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-20% acetone in hexane. Preparation of compound of Formula VI
To a solution of compound of Formula V (1 equiv) in acetonitrile was added solid sodium bicarbonate (5 equiv) and a reagent of Formula R3X (6 equiv) under argon at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield a crude product. The crude product was purified by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-20% acetone in hexane.
Preparation of compound of Formula VII
To a solution of compound of Formula VI (1 equiv) in dichloromethane was added triphosgene (1.5 equiv) with stirring. Then to it was added pyridine (15 equiv) slowly. After complete addition, reaction mixture was stirred under inert atmosphere. Reaction was quenched by addition of water. Reaction mixture was diluted with dichloromethane and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product.
Preparation of compound of Formula VIII
To a solution of a compound of formula VII (1 equiv) in dimethylformamide was added tetramethyl guanidine (2.2 equiv) and reaction mixture was heated. Reaction mixture was cooled to an ambient temperature and water was added and extracted with ethyl acetate. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the desired product.
Preparation of compound of Formula DC
To a solution of compound of Formula VIII (1 equiv) in dichloromethane was added a reagent of Formula R5YCOOH (2.5 equiv), 4-N-dimethylaminopyridine (2.5 equiv) and N, N'-dicyclohexylcarbodiimide (2.5 equiv) was added. Pyridine (4 equiv) was added to it. The whole reaction mixture was stirred and then filtered through celite bed. Filtrate was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product. The crude product was purified by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-20% acetone in hexane.
Preparation of compound of Formula X
To a solution of compound of Formula DC (1 equiv) in dimethylformamide:tetrahydrofuran (3:2) was added N,N'-carbonyldiimidazole (3 equiv), followed by sodium hydride in portions Reaction was quenched by addition of ice cold water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, brine dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product.
Preparation of compound of Formula XI
A compound of Formula X (1 equiv) and a compound of Formula R-W-NH2 (3 equiv) were taken in 10% water in acetonitrile and heated. Reaction mixture was cooled to an ambient temperature; acetonitrile was evaporated under reduced pressure. The resulting residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using 25-30% acetone in hexane to afford the desired product.
Preparation of compound of Formula XII
A solution of compound of Formula XI (560mg, 0.6mmol) in methanol was refluxed. Reaction mixture was cooled to an ambient temperature and methanol was evaporated under reduced pressure. Purification of the solid mass was done over silica gel (thoroughly neutralized triethylamine) using 30-35% acetone in hexane or 2-8% methanol in dichloromethane.
Scheme II
Preparation of compound of Formula XHI
A solution of compound of Formula X (1 mmol) in dry dimethylformamide and hydrazine hydrate (2.0 mmol) was added to it. The reaction mixture was stirred at room temperature for about 1.5 hour. It was quenched with water and extracted in ethyl acetate, washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified over silica gel column to afford the product.
Preparation of compound of Formula XIV
A solution of compound of Formula XHI in methanol was heated at 70°C for about 20 hours. The solvent was removed and the residue was purified over silica gel column to afford the product.
Preparation of compound of Formula XV
A compound of Formula XIV (1.0 mmol) and heterocyclyl alkyl aldehyde (5.0 mmol, (prepared by following the procedure given in WO 00/17218) were dissolved in methanol. Glacial acetic acid (5.0 mmol) was added. The resulting mixture was stirred at room temperature for about 1-2 hour. Sodium cyanoborohydride (5.0 mmol) and glacial acetic and (5.0 mmol) were added to it. The mixture was stirred at room temperature for about 12 hours, solvent was removed, the reaction mixture was extacted with dichloromethane, washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified over silica gel column to afford the product.
The following compounds were prepared by following the above general procedures.
Compound No. 1: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-
imino] erythromycin A
MS (+ ion mode): m/z 900.5 [M+l],
Compound No. 2: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-imidazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 914.6 [M+l],
Compound No. 3: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-imino]erythromycin A MS (+ion mode): m/z 912.6 [M+l],
Compound No. 4: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)-imidazo(4,5-b)-pyridin-3-yl)-
butyl)-imino] erythromycin A
MS (+ ion mode): m/z 966.6 [M+l],
Compound No. 5: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 965.5 [M+l],
Compound No. 6: ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-nitrophenyl acetyl)-5-0-(3'-N-
desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 976.6 [M+l],
Compound No. 7: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-(prop-2-en-yl)-imino]erythromycin A MS (+ ion mode): m/z 844.7 [M+l],
Compound No. 8: ll,12-Dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-imidazol-1 -yl)-butyl)-
imino] erythromycinA
MS (+ ion mode): m/z 870.7 [M+l],
Compound No. 9: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3*-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-imidazol-1 -yl)-butyl)-
imino]erythromycin A
MS (+ ion mode): m/z 870.6 [M+l],
Compound No. 10: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-
imino]erythromycin A
MS (+ ion mode): m/z 920.7 [M+l],
Compound No. 11: ll,12-Dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-imino] erythromycin A
MS (+ion mode): m/z 920.5 [M+l],
Compound No. 12: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)-imidazol-[4,5-b]pyridin-3-yl)-
butyl)-imino]erythromycin A
MS (+ ion mode): m/z 921.6 [M+l],
Compound No. 13: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-( 1 H)-imidazol-[4,5-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ion mode): m/z 921.9 [M+l],
Compound No. 14: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3"-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo-[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 920.8 [M+l],
Compound No. 15: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-indol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 919.6 [M+l],
Compound No. 16: ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ion mode): m/z 946.8 [M+l],
Compound No. 17: ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3*-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(l H)-imidazol-[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 921.8 [M+l],
Compound No. 18: ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-indol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 920.8 [M+l],
Compound No. 19: ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 919.8 [M+l],
Compound No. 20: ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-pyrrolo-[2,3-b]pyridin-l-yl)-butyl)-
imino]erythromycin A
MS (+ ion mode): m/z 920.8 [M+l],
Compound No. 21: ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)-imidazol-[4,5-b]pyridin-3-yl)-
butyl)-imino]erythromycin A
MS (+ion mode): m/z 921.9 [M+l],
Compound No. 22: ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 946.9 [M+l],
Compound No. 23: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3,-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((N1-methyl-N1-pyridin-4-ylmethyl)-2-aminoethyl)-imino] erythromycin A MS (+ion mode): m/z 896.49 [M+l],
Compound No. 24: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-S'-N-ethy^-e-O-methyl-njl-toxycarbonyl-^'-methyl-N^pyridin^-ylmethyl)^-aminoethyl)-imino]erythromycin A MS (+ ion mode): m/z 896.42 [M+l],
Compound No. 25: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-S'-N-ethy^-e-O-methyl-njll-foxycarbonyl-^^methyl-N^pyridin-S-ylmethyl)^-aminoethyl)-imino]erythromycin A MS (+ ion mode): m/z 896.42 [M+l],
Compound No. 26: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-CCN1 -methyl-N1 -quinolin-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A MS (+ ion mode): m/z 946.48 [M+l],
Compound No. 27: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3*-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 932.89 [M+l],
Compound No. 28: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-( 1 H)imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 933.94 [M+l],
Compound No. 29: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)imidazo[4,5-b]pyridin-3-yl)-
butyl)-imino] erythromycin A
MS (+ ion mode): m/z 933.94 [M+l],
Compound No. 30: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3*-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(2-methyl)-benzoimidazo-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 934.79 [M+l],
Compound No. 31: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-iminojerythromycin A MS (+ ion mode): m/z 958.98 [M+l],
Compound No. 32: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-pyridin-2-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 881.78 [M+l],
Compound No. 33: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyridin-4-yl)-butyl)-iminojerythromycin A MS (+ ion mode): m/z 881.85 [M+l],
Compound No. 34: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzoimidazo-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 932.8 [M+l],
Compound No. 35: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 959.83 [M+l],
Compound No. 36: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 933.94 [M+l],
Compound No. 37: ll,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 947.96 [M+l],
Compound No. 38: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-l-yl)-
butyl)-imino]erythromycin A
MS (+ ion mode): m/z 947.96 [M+l],
Compound No. 39: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3 -yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 947.96 [M+l],
Compound No. 40: ll,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-l 2,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 920.96 [M+l],
Compound No. 41: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-propargyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(3H)imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 931.94 [M+l],
Compound No. 42: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acety^-S-O-CS'-N-
desmethyl-3'-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)imidazo[4,5-b]pyridin-3-yl)-
butyl)-imino] erythromycin A
MS (+ ion mode): m/z 933.99 [M+l],
Compound No. 43: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((9-(4-amino-butyl)9H-purin-6-yl)-imino] erythromycin A MS (+ ion mode): m/z 949.83 [M+l],
Compound No. 44: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzoimidazo-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 933.01 [M+l],
Compound No. 45: ll,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 946.81 [M+l],
Compound No. 46: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 958.82 [M+l],
Compound No. 47: ll,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(3H)imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 921.83 [M+l],
Compound No. 48: ll,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3' -N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 921.59 [M+l],
Compound No. 49: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 959.92 [M+l],
Compound No. 50: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-iminojerythromycin A MS (+ ion mode): m/z 932.66 [M+l],
Compound No. 51: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-propargyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzoimidazo-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 930.64 [M+l],
Compound No. 52: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 921.65 [M+l],
Compound No. 53: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(l H)imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 933.63 [M+l],
Compound No. 54: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-
desmethyl-3 '-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 933.7[M+1],
Compound No. 55: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 921.71 [M+l],
Compound No. 56: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3 '-N-propargyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 930.91 [M+l],
Compound No. 57: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-furan-2-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 948.42 [M+l],
Compound No. 58: ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-thiophen-2-yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 964.33 [M+l],
Compound No. 59: ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-( (9-(3-hydrazino-propyl)-9-H-purin-6-yl-4-amino)] erythromycin A MS (+ ion mode): m/z 950.39 [M+l].
Pharmacological activity
Compounds disclosed herein display antibacterial activity in vitro especially against strains which are resistant to macrolides either due to efflux (mef strains) or ribosomal modification (erm) strains. These compounds are useful in the treatment of 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
The 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 C02 incubation (5% C02) 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 108 CFU/ml). The cultures were diluted 10 fold in saline to get inoculum size of approximately 1-2 x 107 organisms/ml.
Preparation of drug concentration
1 mg/ml concentration of stock solution of drugs was prepared in dimethylsulfoxide/distilled
water/solvent given in National Committee for Clinical Laboratory Standards (NCCLS) manual.
Serial two fold dilutions of the compounds and standard drugs were prepared as per NCCLS
manual.
Stock solution was changed according to the need of the experiment.
Preparation of Agar Plates
Two ml of respective drug concentration was added to 18 ml of Molten Mueller Hinton agar to
get the required range, for example 0.015 fog/ml - 16 [ig/ml. For fastidious cultures 1 ml of sheep
blood was added in Molten Mueller Hinton agar.
For control MHA and MHA with 5% sheep blood plates without antibiotic for each set were
prepared. One MHA and MHA with 5% sheep blood plate without antibiotic for determining
quality check for media was prepared.
Preparation of Teflon template
1 JLXI of each culture on each plate was replicated with the help of replicator (Denley's multipoint replicator). The spots were allowed to dry and the plates were incubated for about 18-24 hours at 37°C. Fastidious cultures were incubated at 37 °C in CO2 incubator. The results were noted comparing with the control plates.
Endpoint definition
The concentration of drug at which there was complete disappearance of growth spot or
formation of less than 10 colonies per spot was considered as Minimum Inhibitory Concentration
(MIC).
The MICs of Quality Control (QC) strains were plotted on the QC chart for agar dilution method. If the MICs were within the range, the results interpreted by comparing MICs of standards against all organisms with those of test compounds.
Precautions & Quality Control Measures
Quality Control Strains
Staphylococcus aureus ATCC 29213 Enterococcus faecalis ATCC 29212 Eschericia coli ATCC 25922 Pseudomonas aeruginosa ATCC 27853
All 60 cultures were visually checked for purity.
Media Control: NCCLS disc diffusion assay using lOug 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.
Results: The MICs of compounds of Formula I against some bacterium are shown in Table II and III.
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-S12, Vol. 22 No. 1 (January 2002). (TABLE REMOVED)

WE CLAIM:
1. A compound having the structure of Formula I, as shown in the accompanied
drawings, and its pharmaceutically acceptable salts, pharmaceutically acceptable
solvates, stereoisomers, prodrugs or polymorphs, wherein
R1 represents
o hydrogen
o hydroxyl protecting group
R2 and R3 are independently selected from
o alkyl (with theprovisio that R2 and R3 simultaneously are not methyl) o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle o aralkyl o (heterocycle)alkyl
R4 represents
o alkyl
o alkenyl
o alkynyl
R5 represents
oaryl
o heterocycle
R represents
o no atom
oaryl
o heterocycle
R' represents
o alkyl
0-(CH2)q-U-V
wherein q represents an integer 1 to 4 U represents - alkenyl
- alkynyl
V represents
- hydrogen
- aryl
- heterocycle W represents o alkenyl
o -G(CH2)mJ - wherein m represents an integer 2 to 6 and G represents
- no atom
- -CO
- -CS
- -SO2
- -NR9 o -CR9R10" o -NR9-
o -SO2
wherein R9 and R10 are selected from
o hydrogen
o alkyl
J represents
- no atom
- - N (CH2)n- ,wherein n represents an integer 1 to 4, R9 represents hydrogen or
R9 alkyl
Y represents
o -Q(CH2)k-, wherein k represents an integer 1 to 6, Q represents
o no atom
o -NR9- wherein R9 represents hydrogen or alkyl
o oxygen
one of the hydrogen atom of alkylene chain is optionally replaced by
- alkyl
- hydroxy
alkoxy
Z represents o oxygen
o sulphur
o NOR8 wherein R8 represents hydrogen
- alkyl
- aralkyl

2. A compound according to claim 1 wherein R is optionally substituted heterocycle wherein optional substituent is aryl.
3. A compound according to claim 1 wherein R is optionally substituted monoheterocycle wherein optional substituent is aryl.
4. A compound according to claim 1 wherein R is optionally substituted heterocycle wherein optional substituent is heterocycle.
5. A compound according to claim 1 wherein R is optionally substituted monoheterocycle wherein optional substitutent is heterocycle.
6. A compound according to claim 1 wherein R is pyridin-2-yl.
7. A compound according to claim 1 wherein R is pyridin-3-yl.
8. A compound according to claim 1 wherein R is pyridin-4-yl.

9. A compound according to claim 1 wherein R is imidazolyl.
10. A compound according to claim 1 wherein R is 4-phenylimidazol-l-yl.

11. A compound according to claim 1 wherein R is 4-pyridin-3-yl imidazol-1-yl.
12. A compound according to claim 1 wherein R is 4-furan-2-yl-imidazol-l-yl.
13. A compound according to claim 1 wherein R is 4-thiophen-2-yl-imidazol-l-yl.
14. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein optional substituent is alkyl.
15. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein optional substituent is methyl.
16. A compound according to claim 1 wherein R is quinolin-4-yl.
17. A compound according to claim 1 wherein R is pyrrolo[2,3-b]pyridin-l-yl.
18. A compound according to claim 1 wherein R is (2-methyl) benzoimidazol-1-yl.
19. A compound according to claim 1 wherein R is benzoimidazol-1-yl.
20. A compound according to claim 1 wherein R is benzotriazol-l-yl.
21. A compound according to claim 1 wherein R is 4 -amino-9H-purin-6-yl.
22. A compound according to claim 1 wherein R is indol-1-yl.
23. A compound according to claim 1 wherein R is (lH)-imid£izol-[4,5-b]pyridin-l-yl.
24. A compound according to claim 1 wherein R is (3H)-imidazol-[4,5-b]pyridin-3-yl.
25. A compound according to claim 1 wherein R2 and R3 are respectively methyl and alkyl.
26. A compound according to claim I wherein R2 and R3 are respectively methyl and ethyl.
27. A compound according to claim 1 wherein R2 and R3 are respectively methyl and alkenyl.
28. A compound according to claim 1 wherein R2 and R3 are respectively methyl and propenyl.
29. A compound according to claim 1 wherein R2 and R3 are respectively methyl and
alkynyl.
A comp
propynyl.
A compoi
optional substituent is nitro.
30. A compound according to claim 1 wherein R2 and R3 are respectively methyl and
31. A compound according to claim 1 wherein R5 is optionally substituted aryl wherein
32. A compound according to claim 1 wherein R5 is 3-nitrophenyl.
33. A compound according to claim 1 wherein R5 IS 2-nitrophenyl.
34. A compound according to claim 1 wherein R5 is heterocycle.
35. A compound according to claim 1 wherein R5 IS mono heterocycle.
36. A compound according to claim 1 wherein R5 is monocyclic heterocycle having nitrogen as heteroatom (s).
37. A compound according to claim 1 wherein R5 is 2-pyridine.
38. A compound according to claim 1 wherein R5 is 3-pyridine.
39. A compound according to claim 1 wherein R5 IS 4-pyridine.
40. A compound according to claim 1 wherein W is alkenyl.
41. A compound according to claim 1 wherein W is prop-2-en-yl.
42. A compound according to claim 1 wherein W is -G(CH2)mJ- wherein G is no atom, m is 3 and J is no atom.
43. A compound according to claim 1 wherein W is -G(CH2)mJ- wherein G represents no atom, m is 4 and J represents no atom.
44. A compound according to claim I wherein W is -G(CH2)mJ- wherein G represents no atom, m is 2 and J , wherein R9 is alkyl and n is 1.
45. A compound according to claim 1 wherein W is -G(CH2)mJ- wherein G represents no

atom, m is 2 and J represents R., wherein R9 is methyl and n is 1.
46. A compound according to claim 1 wherein W is -G(CH2)mJ- wherein G represents -NR',wherein R5 is hydrogen m is 3 and J represents no atom.
47. A compound according to claim 1 wherein R1 and Z are hydrogen and oxygen.
respectively.
48. A compound according to claim 1 wherein R' and R4 are alkyl and Y is -Q(CH2)k,
A compound
wherein Q is no atom and k is an integer 1 to 6.
49. A compound according to claim 48 wherein R' and R4 are methyl and ethyl, respectively and Y is -Q(CH2)k, wherein Q is no atom and k is 1.
50. A compound which is:
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((3 -imidazol-1 -yl)-propyl)-imino]erythromycin A (Compound No. 1),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-imidazol-1 -yl)-butyl)-imino] erythromycin A (Compound No. 2),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-imino]erythromycin A (Compound No. 3),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)-imidazo(4,5-b)-pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 4),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 5),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 6),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-nitrophenyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-(prop-2-en-yl)-imino] erythromycin A (Compound No. 7),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-imidazol-1 -yl)-butyl)-imino] erythromycin A (Compound No. 8),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 9),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 10),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzimidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 11),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)-imidazol-[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 12),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-( 1 H)-imidazol-[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 13),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo-[2,3-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 14),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-indol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 15),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 16),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-( 1 H)-imidazol-[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 17),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((4- indol -l-yl)-butyl)-imino]erythromycin A (Compound No. 18),
-11,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-
ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4- benzimidazol -1 -yl)-butyl)-
imino]erythromycin A (Compound No. 19),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo-[2,3-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 20),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(3H)-imidazol-[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 21),
-ll,12-Dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 22),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pvridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,ll-[oxycarbonyl-((N -methyl-N'-pyridin-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 23),
11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-
1,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl :hyl)-6-0-methyl-12,l l-[oxycarbonyl-((N -meth
ethyl)-6-0-methyl-12,l l-[oxycarbonyl-((N -methyl-N -pyridin-2-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 24),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyI-3'-N-ethyl)-6-0-methyl-12,11- [oxycarbonyl-((N' -methyl-N' -pyridin-3 -ylmethyl)-2 -aminoethyl)-imino]erythromycin A (Compound No. 25),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((N'-methyl-N'-quinolin-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 26),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 27),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1 -yl)-butyl)-iminojerythromycin A (Compound No. 28),
-ll,12-dideoxy-3-0-decIadinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 29),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(2-methyl)-benzoimidazo-1 -yl)-butyl)-imino]erythromycin A (Compound No. 30),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 31),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyridin-2-yl)-butyl)-imino]erythromycin A (Compound No. 32),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyridin-4-yl)-butyl)-imino] erythromycin A (Compound No. 33),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-alIyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzoimidazo-1 -yl)-butyl)-imino]erythromycin A (Compound No. 34),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3 -yl)-imidazol-1 -yl)-butyl)-iminojerythromycin A (Compound No. 35),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 36),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 37),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 38),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 39),
-11,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 40),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-propargyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 41),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-iminojerythromycin A (Compound No. 42),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((9-(4-amino-butyl)9H-purin-6-yl)-imino]erythromycin A (Compound No. 43),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzoimidazo-1 -yl)-butyl)-imino]erythromycin A (Compound No. 44),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 45),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 46),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 47),
-11,12-dideoxy-3-0-decladinosyl-3-0-(4-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyI-((4-benzotriazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 48),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-pyridin-3 -yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 49),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 50),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-propargyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzoimidazo-1 -yl)-butyl)-imino]erythromycin A (Compound No. 51),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 52),
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(l H)-imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 53),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-anyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 54),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 55),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-propargyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 56)
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-fiiran-2-yl)-imidazol-1 -yl)-butyl)-iminojerythromycin A (Compound No. 57)
-11,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(4-thiophen-2-yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 58)
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-alIyl)-6-0-methyl-12,11 -[oxycarbonyl-( (9-(3-hydrazino-propyl)-9-H-purin-6-yl-4-amino)]erythromycin A (Compound No. 59) and
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs or polymorphs.
51. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the preceding claims together with pharmaceutically acceptable carrier, excipients or diluents.
52. A method for treating or preventing a mammal suffering from a condition caused by or contributed to by bacterial infection, comprising administering to the said mammal a therapeutically effective amount of a compound of any one of the claims 1-50.
53. A method for treating or preventing a mammal suffering from a condition caused by or contributed to by bacterial infection, comprising administering to the said mammal a therapeutically effective amount of a pharmaceutical composition of claim 51.
54. The method according to claim 52 or 53 wherein the said condition is selected from the group consisting of community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or bone and joint infections, and other bacterial infections, for example, mastitis, catether infection, foreign body or prosthesis infections.
55. The method according to claim 52 or 53 wherein the said bacterium is gram positive, gram negative or anaerobic bacteria.
56. The method according to claim 55 wherein bacterium is selected from the group comprising of Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp.. Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus and Enterobactericeae.
57. The method according to claim 56 wherein the bacterium is cocci.
58. The method according to claim 57 wherein the cocci is drug resistant.
59. A process for preparing a compound of Formula Xn, as shown in Scheme I of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs or polymorphs, wherein
R^ represents
o alkyl (with theprovisio that R5 is not methyl)
o alkenyl
o alkynyl
o cycloalkyl
oaryl
o heterocycle
o aralkyl
o (heterocycle)alkyl
R^ represents oaryl
o heterocycle R represents o no atom oaryl
o heterocycle W represents o alkenyl o -G(CH2)mJ- wherein m represents an integer 2 to 6 and G represents
- no atom
- -CO
- -CS
- -SO2
- -NR^ O-CRV o -NR^-0-SO2
wherein R^ and R"' are selected from
- hydrogen
- alkyl J represents
- no atom
- N (CH2)n-, wherein n represents an integer 1 to 4, R^ represents hydrogen or alkyl
R9
Y represents
o -Q(CH2)k- wherein k represents an integer 1 to 6, Q represents
- no atom
-NR- wherein R represents hydrogen or alkyl
- oxygen
one of the hydrogen atom of alkylene chain is optionally replaced by
- alkyl
- hydroxy alkoxy,
which comprises:
hydrolyzing clarithromycin of Formula H, to give a compound of Formula HI, which on protection with a reagent of Formula R'20 or R'X (wherein X is halogen) gives a compound of Formula IV (wherein R5 IS -COPh), which on desmethylation at 3'-N-dimethyl gives a compound of Formula V, which on alkylation with a reagent of Formula R^CHO, R^aCO or R^X (wherein X is halogen) gives a compound of Formula VI (wherein R5 is the same as defined earlier), which on reaction with a suitable reagent gives a compound of Formula VII,which on reaction with a suitable base gives a compound of Formula VHI, which on reaction with a compound of Formula RYCOOH, (RYC0)20, RYCOX or RYCOOR'" (wherein R'" is leaving group) gives a compound of Formula IX (wherein Y and R^ are the same as defined earlier), which on reaction with N, N'- carbonyl diimidazole gives a compound of Formula X, which on reaction with a compound of Formula R-W-NH2 gives a compound of Formula XI (wherein W and R are the same as defined earlier),which is finally deprotected to give a compound of Formula Xn as shown in the accompanied drawings.
60. The process according to claim 59 wherein the hydrolysis of clarithromycin of Formula 11 to give a compound of Formula HI is carried out in the presence of inorganic or an organic acid selected from the group consisting of hydrochloric acid, sulphuric acid and dichloroacetic acid.
61. The process according to claim 60 wherein the hydrolysis is carried out in hydrochloric acid.
62. The process according to claim 59 wherein the hydroxyl protection of a compound of Formula III to give a compound of Formula IV is carried out in a suitable solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride and ethyl acetate.
63. The process according to claim 62 wherein the hydroxyl protection is carried out in dichloromethane.
64. The process according to claim 59 wherein the hydroxyl protection of a compound of Formula in to give a compound of Formula IV is carried out in the presence of an organic base selected from the group consisting of triethylamine, pyridine, tributylamine and 4-N-dimethylaminopyridine.
65. The process according to claim 64 wherein the protection is carried out in triethylamine.
66. The process according to claim 59 wherein the desmethylation of compound of Formula TV to give a compound of Formula V is carried out in the presence of a demethylating agent selected from the group consisting of N-iodosuccinamide and diisopropylazodicarboxylate.
67. The process according to claim 66 wherein the desmethylation is carried out with N-iodosuccinamide.
68. The process according to claim 59 wherein the desmethylation of compound of Formula IV is carried out in a suitable solvent selected from the group consisting acetonitrile, dichloromethane, dichloroethane and mixture thereof
69. The process according to claim 68 wherein the desmethylation is carried out in acetonitrile and dichloromethane mixture.
70. The process according to claim 59 wherein the quenching of desmethylation is carried out in the presence of a suitable quenching agent selected from the group consisting of potassium carbonate, sodium acetate and sodium bisulphite.
71. The process according to claim 59 wherein the alkylation of a compound of Formula V with a compound of Formula R^X to give a compound of Formula VI is carried out in a suitable solvent selected from the group consisting of dimethylformamide, acetonitrile and tetrahydrofiiran.
72. The process according to claim 71 wherein the alkylation is carried out in acetonitrile.
73. The process according to claim 59 wherein the alkylation of compound of Formula V to give a compound of Formula VI is carried out in the presence of an inorganic or organic base selected from the group consisting of sodium hydrogen carbonate, potassium carbonate, sodium acetate, sodium thiosulfate, sodium hydride, pyridine, triethylamine and diisopropylamine.
74. The process according to claim 73 wherein the alkylation is carried out in sodium bicarbonate.
75. The process according to claim 73 wherein the alkylation is carried out in diisopropylamine.
76. The process according to claim 59 wherein the reaction of compound of Formula VI to give a compound of Formula Vn is carried out in the presence of suitable reagent selected from the group consisting of triphosgene and ethylene dicarbonate.
77. The process according to claim 76 wherein the reaction is carried out in the presence of triphosgene.
78. The process according to claim 59 wherein the reaction of compound of Formula VI is carried out a suitable solvent selected from the group consisting of chloroform, dichloromethane, carbon tetrachloride and dichloroethane.
79. The process according to claim 78 wherein the reaction is carried out in dichloromethane.
80. The process according to claim 59 wherein the reaction of compound of Formula VI is carried out in an organic base selected from the group consisting of triethylamine, pyridine, tributylamine and 4-N-dimethylaminopyridine.
81. The process according to claim 80 wherein the reaction of compound of Formula VI is carried out in the presence of pyridine.
82. The process according to claim 59 wherein the reaction of compound of Formula Vn to give a compound of Formula VEI is carried out in a suitable solvent selected from the group consisting of dimethylformamide, tetrahydrofiiran and dimethylsulphoxide.
83. The process according to claim 82 wherein the reaction is carried out in dimethyformamide.
84. The process according to claim 59 wherein the reaction of compound of Formula VU is carried out in the presence of an organic base selected from the group consisting of tetramethyl guanidine, pyridine and trimethylamine.
85. The process according to claim 84 wherein the reaction is carried out in the presence of tetramethyl guanidine.
86. The process according to claim 59 wherein the reaction of a compound of Formula Vin with a compound of Formula R^YCOOH to give a compound DC is carried out in a suitable solvent selected from the group consisting of dichloromethane, dichloroethane, acetone, ethyl acetate and tetrahydrofuran.
87. The process according to claim 86 wherein the reaction is carried out in dichloromethane.
88. The process according to claim 59 wherein the reaction of a compound of Formula VIII to give a compound IX is carried out in the presence of an inorganic or organic base selected from the group consisting of sodium bicarbonate, potassium carbonate, triethylamine, pyridine, tributylamine and 4-N-dimethylaminopyridine.
89. The process according to claim 88 wherein the reaction is carried out in the presence of pyridine.
90. The process according to claim 59 wherein the reaction of a compound of Formula VIII to give a compound IX is carried out in the presence of an activating agent selected from the group consisting of dicyclohexylcarbodiimide and l-ethyl-3-(3-dimethylaminopropyl)carbodiimode hydrochloride.
91. The process according to claim 90 wherein the reaction is carried out in the presence ofN, N'-dicyclohexylcarbodiimide.
92. The process according to claim 59 wherein the reaction of a compound of Formula IX to give a compound of Formula X is carried out in a suitable solvent selected from the group consisting of dimethylformamide, tetrahydrofuran and mixture thereof
93. The process according to claim 92 wherein the reaction is carried out in dimethylformamide and tetrahydrofuran mixture.
94. The process according to claim 59 wherein the reaction of a compound of Formula IX to give a compound of Formula X is carried out in the presence of an inorganic base selected from the group consisting of sodium hydrogen carbonate, potassium carbonate and sodium hydride.
95. The process according to claim 94 wherein the reaction is carried out in the presence sodium hydride.
96. The process according to claim 59 wherein the reaction of a compoimd of Formula X to give a compound of Formula XI is carried out in a suitable solvent selected from the group consisting of acetonitrile, water, dimethylformamide and mixture thereof
97. The process according to claim 96 wherein the reaction is carried in water and acetonitrile mixture.
98. The process according to claim 59 wherein the deprotection of a compound of Formula XI to give a compound of Formula XII is carried out in the presence of an alcohol selected from the group consisting of methanol, ethanol, propanol and isopropanol.
99. The process according to claim 98 wherein the deprotection is carried out in the presence of methanol.
100. A process for preparing a compound of Formula XV, as shown in Scheme II of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs or polymorphs, wherein R^ represents
o alkyl {with the provisio that R is not methyl) o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle o aralkyl
o (heterocycle)alkyl R^ represents o aryl
o heterocycle R represents o no atom o aryl
o heterocycle
m represents an integer 2 to 6 Y represents o -Q(CH2)k- wherein k represents an integer 1 to 6, Q represents
- no atom
-NR- wherein R represents hydrogen or alkyl
- oxygen
one of the hydrogen atom of alkylene chain is optionally replaced by
- alkyl
- hydroxy alkoxy,
which method comprises reacting a compound of Formula X (Scheme I) with hydrazine hydrate to give a compound of Formula XHI, which on deprotection gives a compound of Formula XIV, which is finally reacted with a compound of Formula R(CH2)mCH0 to give a compound of Formula XV( wherein R and m are the same as defined earlier) as shown in the accompanied drawings.
101. The process according to claim 100 wherein the reaction of a compound of Formula X with hydrazine hydrate to give a compound of Formula Xni is carried out in a solvent selected from the group consisting of dimethylformamide, tetrahydrofiiran and dimethylsulphoxide.
102. The process according to claim 101 wherein the reaction is carried out in dimethylformamide.
103. The process according to claim 100 wherein the deprotection of a compound of Formula XIII to give a compound of Formula XIV is carried out in a solvent selected from the group consisting of methanol, ethanol, propanol and isopropanol.
104. The process according to claim 103 wherein the deprotection is carried out in methanol.
105. The process according to claim 100 wherein the reaction of a compound of Formula XIV with a compound of Formula R(CH2)mCH0 to give a compound of Formula XV is carried out in a solvent selected from the group consisting of methanol, ethanol, propanol and isopropanol.
106. The process according to claim 105 wherein the reaction is carried out in methanol.
107. The process according to claim 100 wherein the reaction of a compound of Formula XIV to give a compound of Formula XV is carried out in the presence of an organic acid selected from the group consisting of acetic acid and dichloroacetic acid.
108. The process according to claim 107 wherein the reaction is carried out in the presence of acetic acid.
109. The process according to claim 100 wherein the reaction of a compound of Formula XIV to give a compound of Formula XV is carried out in the presence
of a reducing agent selected from the group consisting of sodiimi borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.
110. The process according to claim 109 wherein the reaction is carried out in the presence of sodium cyanoborohydride.
111. The processes for the preparation of compounds of Formulae XII and XV, substantially as herein described and illustrated by example hereip.