KETOLIDE DERIVATIVES AS ANTIBACTERIAL AGENTS FIELD OF INVENTION
The present invention provides ketolide 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, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae. Processes for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and method of treating bacterial infections are also provided.
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, 1984, 247: 688; Omura, S et al, J. Med. Chem, 1987, 30, 1943). Various erythromycin A derivatives have been prepared to overcome the acid instability and other problems associated with it.
Roxithromycin, clarithromycin and azithromycin 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 favourable 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. Ketolides exhibit greater efficacy and safety, have
broader spectrum of activities, and are particularly effective against resistant pathogens, hence have been developed as next generation macrolides.
U.S. Patent No. 5, 635, 485 discloses erythromycin compounds that are useful in the treatment of bacterial infections in warm-blooded animals.
U.S. Patent No. 5, 866, 549 discloses novel semi-synthetic macrolides having antibacterial activity, more particularly, 6-0-substituted erythromycin ketolide derivatives and method of treating bacterial infections.
WO 00/62783 discloses ketolide antibacterials that are useful in the treatment of bacterial and protozoal infections and in the treatment of other conditions involving gastric motility.
WO 00/44761 discloses ketolide antibiotics useful as antibacterial and antiprotozoal agents in mammals.
U.S. Patent No. 5,747,467 discloses erythromycin and novel antibacterial composition and method of treating bacterial infection in warm-blooded animals.
U.S. Patent No. 6,433,151 discloses erythromycin derivatives and their use as medicament for the treatment of infection caused by gram positive bacteria, Haemophilus influenzae, Moraxalla spp.
U.S. Patent Nos. 6,458,771 and 6,399,582 disclose ketolide antibacterials useful in the treatment of bacterial and protozoal infections and in the treatment of other conditions involving gastric motility.
U.S. Patent No. 6,472,372 discloses 6-O-carbamoyl ketolide antibacterials and methods of treating bacterial infections.
U.S. Patent Application Nos. 2002/0115621 and 2003/0013665 disclose macrolide compounds that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well in fish and birds.
Other references disclosing ketolide compounds include Alexis Denis and Alain Bonnefoy, Drugs of the Future, 26 (10), 975-84 (2001) Champney W. S., et al.. Current Microbiology, 42, 203-10 (2001)
SUMMARY OF THE INVENTION
The present invention provides ketolide derivatives, which can be used in the treatment or prevention of bacterial infection, and processes for the synthesis of these compounds.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs of these compounds having same type of activity are also provided.
Pharmaceutical compositions containing the 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.
hi 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 R1 can be —hydrogen
—hydroxyl protecting group R2 and R3 can independently be selected from
— alkyl (with theprovisio that R2 and R3 simultaneously are not methyl) —alkenyl —alkynyl —cycloalkyl —aryl
—heterocycle —aralkyl
—(heterocycle)alkyl —COR" , wherein R11 Can represent o hydrogen o alkyl o aralkyl
W can be
— alkenyl
G(CH2)qJ- wherein q can represent an integer 2 to 6 and G can be
o no atom o -CO o -CS o -SO2
- -CRR'°
- -NR-
- -SO2
wherein R2 and R can be selected fi'om o hydrogen o alkyl and J can be
— no atom
,wherein R2 and R are the same as defined earlier.
o hydrogen
o alkyl
o alkylene
o alkynyl
Q O
o COR , wherein R represents alkyl,aryl or heterocycle
Q O
o -(CH2)m-R , wherein m is the same as defined earlier and R represents alkyl,aryl or heterocycle R can be —aryl
—heterocycle R can be —alkyl —alkenyl —alkynyl R' can be
—alkyl
- -(CH2)r-U-V
wherein r can represent an integer 1 to 4 U can be
o alkenyl
o alkynyl
V can be
o no atom o alkyl o aryl o heterocycle
Y can be
—halogen
—cyano
—alkyl
Z can be —oxygen —sulphur
— NOR' ' wherein R' ' is the same as defined earlier.
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, for example, 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, for example, mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease.
hi accordance with a third aspect, there are 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, heterocycle, aralkyl, (heterocycle)alkyl, cycloalkoxy, -NHCOR -NHCOOR -OCOR or -COR wherein R* 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 alkyl, 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 protected" includes, but is not limited to, acyl, aroyl, alkyl, aryl, butyldiphenylsilyl, methoxymethyl and methylthiomethyl, and the like.
As used herein the term "thio" refers to the group -SH.
As used herein the term "alkoxy" stands for a group 0-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 is alkyl or cycloalkyl.
As used herein the term "haloalkyl" refers to alkyl of which one or more hydrogen (s) is/are replaced by halogen.
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) wherein the said hetero atom (s) is/ are selected from the group comprising of nitrogen, sulphur and oxygen, ring system is attached through heteroatom or carbon and the ring system includes mono, bi or tricyclic. Examples of heterocycles include, but not limited to, azetidiny], benzoimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothiazinyl, benzotriazolyl, dihydroimidazolyl, dihydropyranyl, dihydrofiiranyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazopyridinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, napthyridinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, purinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrrolopyridinyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl and thiazolyl, and 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, pyridyl methyl 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 amino, hydroxy, halogen, nitro, mercapto, cyano, alkyl, haloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl alkyl, alkoxy, thioalkyl, -NRR -CONRR, -COOR -CONHR -OCOR, -COR -NHSOaR2 and -S02NHR, wherein R2 and R2 are independently selected from the group comprising of hydrogen and alkyl.
As used herein the term "polymorphs" includes all crystalline form and amorphous form for compounds described herein, hi addition, some of the compounds described herein may form solvates with water (i-e hydrate, hemihydrate or sesquihydrate) or common organic solvents. Such solvates are also encompassed within the scope of this invention.

The phrase "pharmaceutically acceptable salts" denotes salts of the free base, which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. Suitable pharmaceutically acceptable salts may be prepared from an inorganic or organic acid. Example of such inorganic acids include, but not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous (nitrile salt), nitric (nitrate salt), carbonic, sulfuric, phosphoric acid and like. Appropriate organic acids include, but not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fiimeric, 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.
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 Scheme I, n, HI and rV of the accompanied drawings. Scheme I
The compound of Formula XrH can be prepared according to Scheme I, as shown in the accompanied drawing. Thus, clarithromycin of Formula n is hydrolyzed to give a compound of Formula III, which on protection with a reagent of Formula R'IO or R'X (wherein X is halogen) gives a compound of Formula IV (wherein R'=COPh), which on desmethylation at 3'-N-dimethyl group gives a compound of Formula V, which on alkylation with a reagent of Formula
T -5 -1 T
RXHO, R 2CO or R'X gives a compound of Formula VI (wherein R is the same as defined earlier), which on reaction with a reagent, for example, triphosgene or ethylene dicarbonate gives a compound of Formula Vn, which on reaction with a organic base, for example, tetramethyl guanidine or trimethylamine gives a compound of Formula VIH, which on oxidation gives a compound of Formula IX, which on reaction with N,N'-carbanoyl 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 on fluorination gives a compound of Formula Xn, which is finally deprotected to give a compound of Formula XIII.
The hydrolysis of clarithromycin of Formula 11 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 with a reagent of Formula R20 or R'X to give a compound of Formula IV can be carried out in a solvent, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride or ethyl acetate.
The hydroxyl protection of a compound of Formula HI with a reagent of Formula R'20 or R'X can be carried out in the presence of an organic base, for example, triethylamine, pyridine, tributylamine or 4-(N-dimethylamino) pyridine.
The desmethylation of a compound of Formula IV to give a compound of Formula V can be carried out in the presence of a desmethylating agent, for example, N-iodosuccinimide or diisopropylazodicarboxylate.
The desmethylation of a compound of Formula IV can be carried out in a 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 quenching agent, for example, sodium bisulphite, sodium carbonate, potassium carbonate, sodium acetate or mixture thereof
The alkylation of a compound of Formula V with a reagent of Formula RCHO, R2C0 or R'X to give a compound of Formula VI can be carried out in a solvent, for example, dimethylformamide, acetonitrile, methanol, acetone, tetrahydrofuran or mixture thereof
The alkylation of a compound of Formula V can be carried out in an inorganic or organic base, for example, sodium hydrogen carbonate, potassium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate or diisopropyl ethylamine.
The alkylation of a compound of Formula V with a reagent of Formula R CHO can also be carried out 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 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 a solvent, for example, chloroform, dichloromethane, carbon tetrachloride or dichloroethane.
The reaction of a compound of Formula VI to give a compound of Formula VII can be carried out in the presence of an organic base, for example, triethylamine, pyridine, tributylamine or 4-(N-dimethylamino) pyridine.
The reaction of a compound of Formula VII to give a compound of Formula VIE can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran or dimethylsulphoxide.
The oxidation of a compound of Formula VIE to give a compound of Formula DC can be carried out with an oxidizing agent, for example, Dess-Martin periodinane, N-chloro succinimide
or l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. N-Chlorosuccinamide can be used in combination with dimethyl sulphide and l-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride can be used in combination with dimethylsulfoxide.
The oxidation of a compound of Formula Vin to give a compound of Formula IX can be carried out in a solvent, for example, chloroform, dichloromethane, carbon tetrachloride, dimethylsulfoxide or dichloroethane.
The reaction of a compound of Formula DC with N,N'-carbonyl dimidazol to give a compound of Formula X can be carried out in a solvent, for example, dimethylformamide, acetonitrile, tetrahydrofuran or mixture thereof
The reaction of a compound of Formula IX with N,N'-carbonyl dimidazol can be carried out in an inorganic base, for example, sodium hydrogen carbonate, sodium acetate, sodium thiosulphate, 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 solvent system, for example, acetonitrile/water or dimethylformamide/water.
The fluorination of a compound of Formula XI to give a compound of Formula Xn can be carried out with a fluorinating agent, for example, N-fluorobenzene sulfonimide or selectfluor.
The fluorination of a compound of Formula XI can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran or dimethylsulphoxide.
The fluorination of a compound of Formula XI can be carried out in the presence of an inorganic base, for example, potassium carbonate, sodium hydride, sodium acetate, sodium thiosulphate or potassium tert-butoxide.
The deprotection of a compound of Formula Xn to give a compound of Formula XHI can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol.
Scheme n
The compound of Formula Xin can also be prepared according to Scheme n, as shown in the accompanied drawing. Thus, a compound of Formula IV is reacted with a reagent, for example, triphosgene or ethylene dicarbonate to give a compound of Formula XIV, which on
reaction with a organic base, for example, tetramethyl guanidine or trimethyl amine gives a compound of Formula XV, which on oxidation gives a compound of Formula XVI, which on desmethylation at 3'-N-dimethyl group gives a compound of Formula XVII, which on alkylation with a reagent of Formula RCHO, R2 CO or RX (wherein X, halogen) gives a compound of Formula IX (wherein R is the same as defined earlier), which on fluorination gives a compound of Formula XVIII, which on reaction with N,N'-carbonyl diimidazol gives a compound of Formula XIX, which on reaction with a compound of Formula R-W-NH2 gives a compound of Formula XII (wherein W and R are the same as defined earlier), which is finally deprotected to give a compound of Formula XIII.
The reaction of a compound of Formula IV to give a compound of Formula XIV can be carried out in a solvent, for example, dichloromethane, carbon tetrachloride or dichloroethane.
The reaction of a compound of Formula IV to give a compound of Formula XIV can be carried out in the presence of an organic base, for example, triethylamine, pyridine, tributylamine or 4-(N-dimethylamino) pyridine.
The reaction of a compound of Formula XIV to give a compound of Formula XV can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran or dimethylsulphoxide.
The oxidation of a compound of Formula XV to give a compound of Formula XVI can be carried out with an oxidizing agent, for example, Dess-Martin periodinane, N-chlorosuccinimide or l-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride, heterocycle, aralkyl, (heterocycle)alkyl.
The oxidation of a compound of Formula XV to give a compound of Formula XVI can be carried out in a solvent, for example, chloroform, dichloromethane, carbon tetrachloride, dimethylsulphoxide or dichloroethane.
The desmethylation of a compound of Formula XVI to give a compound of Formula XVII can be carried out in the presence of a desmethylating agent, for example, N-iodo succinimide or diisopropyl azodicarboxylate.
The desmethylation of a compound of Formula XVI to give a compound of Formula XVII can be carried out in a 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 quenching agent, for example, sodium bisulphite, sodium carbonate, potassium carbonate, sodium acetate or mixture thereof
The alkylation of a compound of Formula XVn with a reagent of Formula RCHO, R2^ CO or R' X to give a compound of Formula IX can be carried out in a solvent, for example, dimethylformamide, acetonitrile, methanol, acetone, tetrahydrofliran or mixture thereof
The alkylation of a compound of Formula XVn can be carried out in the presence of an inorganic or organic base, for example, sodium hydrogen carbonate, potassium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate or diisopropylethylamine.
The fluorination of a compound of Formula XVII to give a compound of Formula XVni can be carried out with a fluorinating agent, for example, N-fluorobenzene sulfonimide or selectfluor.
The fluorination of a compound of Formula XVn can be carried out in a solvent, for example, dimethylformamide, tetrahydrofliran or dimethylsulphoxide.
The fluorination of a compound of Formula XVn can be carried out in the presence of an inorganic base, for example, potassium carbonate, sodium hydride, sodium acetate, sodium thiosulphate or potassium tert-butoxide.
The reaction of a compound of Formula XVIII with N,N'-carbonyl diimidazol to give a compound of Formula XIX can be carried out in a solvent, for example, dimethylformamide, acetonitrile, tetrahydrofliran or mixture thereof
The reaction of a compound of Formula XVin with N,N'-carbonyldiimidazol can be carried out in the presence of an inorganic base, for example, sodium hydrogen carbonate, potassium carbonate, sodium acetate, sodium thiosulphate or sodium hydride.
The reaction of a compound of Formula XIX with a compound of Formula R-W-NH2 to give a compound of Formula XII can be carried out in a solvent system, for example, acetonitrile/water or dimethylformamide/water.
The deprotection of a compound of Formula Xn to give a compound of Formula XHI can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol.
Scheme III
A compound of Formula XIII can also be prepared according to Scheme in, as shown in the accompanied drawing. Thus, a compound of Formula XVI is fluorinated to give a compound of Formula XX, which on reaction with N,N'-carbanoyl diimidazole gives a compound of Formula XXI, which on reaction with a compound of Formula R-W-NH2 gives a compound of Formula XXII (R & W are the same as defined earlier), which on deprotection gives a compound of Formula XXIQ, which on desmethylation at 3'-N-dimethyl group gives a compound of Formula XXIV, which is alkylated with a reagent of Formula RCHO, R2C0 or RX (wherein X is halogen) to give a compound of Formula XIII (wherein R is the same as defined earlier).
The fluorination of a compound of Formula XVI to give a compound of Formula XX can be carried out with a fluorinating agent, for example, N-fluorobenzene sulfonimide or selectfluor.
The fluorination of a compound of Formula XVI to give a compound of Formula XX can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran or dimethyl sulphoxide.
The fluorination of a compound of Formula XVI can be carried out in the presence of an inorganic base, for example, potassium carbonate, sodium hydride, sodium acetate, sodium thiosulphate or potassium tert-butoxide.
The reaction of a compound of Formula XX with N,N'-carbonyl diimidazol to give a compound of Formula XXI can be carried out in a solvent, for example, dimethylformamide, tetrahydrofiiran, acetonitrile or mixture thereof
The reaction of a compound of Formula XX with N, N'-carbonyl diimidazol can be carried out in the presence of an inorganic base, for example, sodium hydrogen carbonate, potassium carbonate, sodium acetate, sodium thiosulphate or sodium hydride.
The reaction of a compound of Formula XXI with a compound of Formula R-W-NH2 to give a compound of Formula XXn can be carried out in a solvent system, for example, acetonitrile/water or dimethylformamide/water.
The deprotection of a compound of Formula XXn to give a compound of Formula XXm can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol.
The desmethylation of a compound of Formula XXIH to give a compound of Formula XXrV can be carried out in a solvent, for example, acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate or mixture thereof
The desmethylation of a compound of Formula XXni to give a compound of Formula XXrV can be carried out in the presence of a desmethylating agent, for example, N-iodo succinimide or diisopropyl azodicarboxylate.
The quenching of desmethylation reaction can be carried out in the presence of a quenching agent, for example, sodium bisulphite, sodium carbonate, potassium carbonate, sodium acetate or mixture thereof
The alkylation of a compound of Formula XXIV with a reagent of Formula R CHO, R 2
■J
CO or R'X to give a compound of Formula Xm can be carried out in a solvent, for example, dimethylformamide, acetonitrile, methanol, acetone, tetrahydrofuran or mixture thereof.
The alkylation of a compound of Formula XXIV can be carried out in the presence of an inorganic or organic base, for example, sodium hydrogen carbonate, potassium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate or diisopropyl ethylamine.
Scheme IV
The compound of Formula XIII can also be prepared according to Scheme IV, as shown in the accompanied drawing. Thus, a compound of Formula XX (wherein R' is COPh) is deprotected to give a compound of Formula XXV, which on desmethylation at 3'-N-dimethyl group gives a compound of Formula XXVI, which on alkylation with a reagent of Formula RCHO, RiCHO or RX (X is halogen) gives a compound of Formula XXVH (R is the same as defined earlier), which on protection with a reagent of Formula R'20 or RX (wherein X is halogen) gives a compound of Formula XVEI (wherein R' is COCH3) which on reaction with N,N'-carbonyl diimidazol gives a compound of Formula XIX, which on reaction with a compound of Formula R-W-NH2 gives a compound of Formula Xn (R is the same as defined earlier), which is finally deprotected to give a compound of Formula Xin.
The deprotection of a compound of Formula XX to give a compound of Formula XXV can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol.
The desmethylation of a compound of Formula XXV to give a compound of Formula XXVI can be carried out in the presence of a desmethylating agent, for example, N-iodosuccinimide or diisopropyl azodicarboxylate.
The desmethylation of a compound of Formula XXV can be carried out in a 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 quenching agent, for example, sodium bisulphite, sodium carbonate, potassium carbonate, sodium acetate or mixture thereof
The alkylation of a compound of Formula XXVI with a reagent of Formula R CHO, R 2CO on R'X to give a compound of Formula XXVn can be carried out in a solvent, for example, dimethylformamide, acetonitrile, tetrahydrofuran, acetone, methanol or mixture thereof
The alkylation of a compound of Formula XXVI can be carried out in the presence of an inorganic or organic base, for example, sodium hydrogen carbonate, potassium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate or diisopropyl ethylamine.
The hydroxyl protection of a compound of Formula XXVn with a reagent of Formula R'20 or R'X to give a compound of Formula XVin can be carried out in a solvent, for example, dichloromethane, dichloroethane,carbon tetrachloride,chloroform or acetone.
The hydroxyl protection of a compound of Formula XXVn with a reagent of Formula R'20 or R'X can be carried out in the presence of an inorganic base, for example, potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate.
The reaction of a compound of Formula XVm with N, N'-carbonyl diimidazol to give a compound of Formula XIX can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran, acetonitrile or mixture thereof
The reaction of a compound of Formula XVin with N, N'-carbonyldiimidazol can be carried out in the presence of an inorganic base, for example, sodium hydrogen carbonate, potassium carbonate, sodium acetate, sodium thiosulphate or sodium hydride.
The reaction of a compound of Formula XIX with a compound of Formula R-W-NH2 to give a compound of Formula XII can be carried out in a solvent system, for example, acetonitrile/water or dimethylformamide/water.
The reaction of a compound of Formula Xn to give a compound of Formula Xin can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol.
In the above sechemes, where the specific bases, oxidizing agents, solvents, etc., are mentioned, it is to be understood that other bases, oxidizing 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).
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((3-imidazol-l-yl)-propyl)-imino]erythromycin A(Compound No. 1),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0x0-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A (Compound No.2),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l 1,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0x0-12,11 -[oxycarbonyl-((4-(3H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A (Compound No.3),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-benzoimidazol-l-yl)-butyl)-imino]erythromycin A (Compound No.
4),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-imidazol-l-yl)-butyl)-imino]erythromycin A (CompoundNo. 5),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((3-imidazol-l-yl)-propyl)-imino]erythromycin A (Compound No. 6),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((3-imidazol-l-yl)-propyl)-imino]erythromycin A (Compound No.7),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-n-propyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((3-imidazol-l-yl)-propyl)-imino]erythromycin A (Compound No. 8),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-n-propyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-benzoimidazol-l-yl)-butyl)-imino]erythromycin A (Compound No.9),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-pyrrolo-(2,3-b)pyridin-l-yl)-butyl)-imino]erythromycin A (Compound No. 10),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-
3-0X0-12,11 -[oxycarbony]-((4-pyrrolo-(2,3-b)pyridin-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 11),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-benzoimidazol-l-yl)-butyl)-imino]erythromycin A (Compound No. 12),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-
methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A
(Compound No. 13),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-n-propyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-imidazol-l-yl)-butyl)-imino]erythromycin A (Compound No.l4),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-pyrrolo-(2,3-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 15),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A (Compound 16),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-purin-9-yl)-butyl)-imino]erythromycin A (Compound No. 17),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A (Compound No. 18),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-(4-(4-pyridin-3-yl-imidazol-1 -yl)-butyl)-imino]eiythroinycin A
(Compound No. 19),
-2a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((N'-methyl-N'-quinolin-4-ylmethyl)-2-aminoethyl)-iminojerythromycin A (Compound No. 20 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l 1,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((N'-methyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 21),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((N'-methyl-N-pyridine-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 22 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((N'-methyl-N'-pyridine-2-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 23 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((N'-methyl-N'-pyridine-2-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 24 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((N'-methyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 25 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((N'-methyl-N'-pyridine-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 26),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((N'-methyl-N'-quinoline-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No.27 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino]erythromycin (Compound No. 28 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((N'-acetyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No.29 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((N'-pyridme-3-ylmethyl)-2-aminoethyl)-imino]erythromycin A
(Compound No.30 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((N'-acetyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 31),
-2-a-Fluoro-5-0-(3'-N-desmethyI-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N',N'-di-pyridine-3-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 32),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((N',N'-di-pyridine-3-ylmethyl)-2-aminoethyl)-imino]erythromycin A (Compound No. 33 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-quinolin-3-yl)-butyl)-imino]erythromycin A (Compound No. 34),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-quinolin-8-yl)-butyl)-imino]erythromycin A (Compound No. 35 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-pyridin-2-yl)-butyl)-imino]erythromycin A (Compound No.36 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 37 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-pyridin-4-yl)-butyl)-imino]erythromycin A (Compound No. 38 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-pyridin-2-yl)-butyl)-imino]erythromycin A (Compound No. 39),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-pyridin-4-yl)-butyl)-imino]erythromycin A (Compound No. 40 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-pyridin-3-yl)-pentyl)-immo]erythromycin A (Compound No.41 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 42 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-indol-l-yl)-butyl)-imino]erythromycin A (Compound No. 43 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyI-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No.44),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-(5-nitro)-indol-l-yl)-butyl)-imino]erythromycin A (Compound No. 45),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-c]pyridin-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 46),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-benzotriazol-2-yl)-butyl)-imino]erythromycin A (Compound No. 47
),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(3H)-imidazo[4,5-c]pyridin-3-yl)-butyl)-imino]erythromycin A
(Compound No. 48),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-l 1,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-phenyl)-imidazol-l-yl)-butyl)-imino]erythromycin A (Compound No. 49),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3 '-N-cyclopropyl)-11,12-dideoxy-3-0-decladinosyl-6-0-
methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 50),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-
methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-2-yl)-butyl)-imino]erythromycin A
(Compound No. 51 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imdazo[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 52),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-indol-l-yl)-butyl)-imino]erythromycin A (Compound No.
53),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-benzotriazol-l-yl)-butyl)-imino]erythromycin A (Compound No. 54
),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-benzoimidazol-l-yl)-butyl)-imino]erythromycin A (Compound No.
55),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 56),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-
3-0X0-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 57),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-benzotriazol-2-yl)-butyl)-imino]erythromycin A (Compound No.
58),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-indol-l-yl)-butyl)-imino]erythromycin A (Compound No. 59),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 60),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-(5-nitro)-indol-l-yl)-butyl)-imino]erythromycin A (Compound No. 61 ),
-2-a-Fluoro-5-0-(3'-N-desmethyI-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decIadinosyl-6-0-
methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-nitro)-indol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 62),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-(5-fluoro)-indol-l-yl)-butyl)-imino]erythromycin A (Compound No.63),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-benzotriazol-l-yl)-butyl)-imino]erythromycin A (Compound No. 64
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(2-methyl)-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A
(Compound No. 65 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(2-ethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 66),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-benzotriazol-l-yl)-butyl)-imino]erythromycin A (Compound No.
67),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(2-ethyl)-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A
(Compound No. 68),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl-imidazol)-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 69 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(2-methyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 70),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin- l-yl)-butyl)-imino]erythromycin A
(Compound No. 71 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1 -yl)-butyI)-imino] erythromycin (Compound No. 72),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-iminojerythromycin A (Compound No. 73 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-nitro)-indol-1 -yl)-butyl)-imino] erythromycin (Compound No. 74),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-(2-pyridin-3-ylmethyl)-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 75),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-(2-pyridin-3-ylmethyl)-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 76 ),
-2-a-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3 -
0X0-12,11 -[oxycarbonyl-((4-(2-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 77),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-(5-fluoro)-indol-l-yl)-butyl)-imino]erythromycin A (Compound No. 78),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-(5,6-dimethyl)-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 79),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-(5,6-dimethyl)-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 80),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,1 l-[oxycarbonyl-((4-(3H)-imidazo[4,5-c]pyridin-3-yl)-butyl)-imino]erythromycin A
(Compound No. 81 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-(2-methyl)-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 82),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 - [oxycarbonyl-((4-(2-methyl)-(3 H)-imidazo [4,5 -b]pyridin-3 -yl)-butyl)-imino]erythromycin A (Compound No. 83 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-c]pyridin-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 84 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((9-(4-amino-butyl)-9H-purin-6-yl)-imino]erythromycin A (Compound No. 85 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(2-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No.86 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyI-((4-benzoimidazol-l-yl)-butyl)-imino]erytliromycin A (Compound No.
87),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-ll,12-dideoxy-3-0-decladinosyl-6-
0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-
imino]erythromycin A (Compound No. 88 ),
-2-a-Fluoro-5-0-(3'-N-desmethyI-3'-N-cyclopropylmethyl)-ll,12-dideoxy-3-0-decIadinosyl-6-
O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 89),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-ll,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 90),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A (Compound No. 91 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-
methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No.92 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-
methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 93 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A (Compound No. 94 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-(2-trifluoromethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A (Compound No. 95 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(4,5-diphenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 96),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(4,5-diphenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No.97),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 98),
-2-a-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-cyclopropylmethyl)-11,12-dideoxy-3 -O-decladinosyI-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 99),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-ll,12-dideoxy-3-0-decladinosyl-6-
O-methyl-3 -oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino]erythromycin A
(Compound No. 100),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-ll,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 101),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-buty])-imino] erythromycin A
(Compound No. 102),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A
(Compound No. 103 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 - [oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino] erythromycin A (Compound No. 104),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A (Compound No. 105),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,1 l-[oxycarbonyl-((4-(3,5-diphenyl)-pyrazol-l-yl)-butyl)-imino]erythromycin A
(Compound No. 106),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-pyridn-3-yl)-imidazol-l-yl)-butyl)-imino]erythromycin A (Compound No. 107 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 108 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,1 l-[oxycarbonyl-((4-(3,5-diphenyl)-pyrazol-l-yl)-butyl)-imino]erythromycin A
(Compound No. 109),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-ll,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A (Compound No. 110),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-
0X0-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazo)-1 -yl)-butyl)-imino] erythromycin A
(Compound No. Ill),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((4-(4-(2,4-difluoro)-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A (Compound No. 112),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 - [oxycarbonyl-((4-(4-(2,4-difluoro)-phenyl)-imidazol)-1 -yl)-butyl)-imino]erythromycin A (Compound No.l 13 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-allyI)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-(4-(2,4-difluoro)-phenyl)-imidazol)-l -yl)-butyl)-imino]erythromycin A (Compound No. 114 ),
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl~(4-((4-furan-2-yl)-imidazol-l-yl)-butyl)-imino] erythromycin A (Compound No. 115).
(FORMULA REMOVED)
(wherein R1=R2= CH3 ,R4- C2H5, R1=H, Z=0, Y=F)
(TABLE REMOVED)
is the point of attachment
Because of their antibacterial activity, the compounds described herein may be administered to an animal for treatment orally, topically, rectally, intemasally, or by parenteral route. The pharmaceutical compositions of the present invention comprise a pharmaceutically effective amount of compounds described herein formulated together with one or more pharmaceutically acceptable carriers.
Solid form preparation for oral administrations include 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 hi the case of capsules, tablets, pills, the dosage form may also comprise buff erring 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, com, germ, olive, castor and 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.
hijectable 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 include 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.
Examples set forth below demonstrates 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
Preparation of R-W-NH2
(a) when W= -(CH2)4 -
Preparation of 4-(3H)-imidazol [4,5-b] pyridin-3-yl-butylamine
It was prepared by following the procedure given in US Patent No. 5,635,485.
(b) when W=-(CH2)2-NH-CH2-
Preparation of N*l*-pyridin-4-yl-methylethane-l, 2-diamine
To a solution of ethylene diamine (467.2mmol) in methanol (50ml) was added pyridin-3-carboxaldehyde (46.7mmol) at 0-5 °C. The reaction mixture was allowed to come to ambient temperature and added sodium borohydride (1.5g, 46.7mmol) in portion, and the whole reaction mixture was stirred for about 4 h. The solvent was removed under reduced pressure to get 5.2g of crude product. The crude product was purified by silica gel column chromatography using 10% methanol-dichloromethane with 5% triethyl amine.
(c) when W=-(CH2)2-N (CH3)-CH2-
Step I: Preparation of methylpyridin-4-ylmethylamine
To a solution of pyridine 4-carbaldehyde (57.3mmol), in methanol (90ml) was added 40% methyl amine (68.7 mmol) at 0-5°C and stirred for about 15min. followed by addition of
sodium borohydride (57.3mmol). Reaction mixture was refluxed for about 1 h. Then it was cooled to ambient temperature and solvent was removed under reduced pressure. To the resulting residue, water was added and extraction was carried out with dichloromethane. All dichloromethane layers were mixed and washed with water, brine, dried over anhydrous sodium sulphate, solvent was evaporated under reduced pressure to give a crude product.
Step II: Preparation of 2-[2-(methylpyridin-4-ylmethylamino) ethylisoindoIe-1, 3-dione
To a solution of N*l*-pyridin-4-yl-methylethane-l,2-diamine (55.2mmol) in dimethylformamide (50ml) was added potassium carbonate (55.2mmol) and 2-bromoethylphthalimide (66.2mmol). The resulting reaction mixture was heated at 80 °C for about 16h. Reaction mixture was cooled to ambient temperature and poured into water, extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give product. Step ni: Preparation of N* 1 *-methyl-N* 1 *-pvridin-4-vlmethYlethane-1, 2-diamine
To a solution of 2-[2-(methylpyridin-4-ylmethylamino) ethylisoindole-1, 3-dione (20.28mmol) in methanol (210ml) was added hydrazine hydrate (lO.Hg, 202.8mmol). The reaction mixture was refluxed for about 2 h. Then reaction mixture was cooled to ambient temperature and white crystalline solid was filtered, washed with methanol (50ml), solvent was removed from filtrate. To the resulting residue diethyl ether was added, and stirring was carried out for about 30min. The solid was filtered and washed with ether. The filtrate was concentrated under reduced pressure to afford oily product. Scheme I Preparation of compound of Formula HI
To an aqueous solution of hydrochloric acid was added clarithromycin (25 gm, 33.4 mmol) at an ambient temperature in portion. The reaction mixture was neutralized with solid sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. Organic layer was washed with water, brine, and dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to afford crude product. The crude product was crystallized by using ethyl acetate and hexane.
Preparation of compound of Formula IV
To a solution of compound of Formula HI (1 equiv) in dichloromethane was added benzoic anhydride (2.5 equiv) followed by triethylamine (6 equiv) and stirred at an ambient temperature. The reaction was quenched by addition of sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane, washed successively with water, brine, and dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to give crude product. The crude product obtained was crystallized by using ethyl acetate and 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) and the reaction mixture was allowed to attain an ambient temperature and stirred. The reaction mixture was stirred with a sodium bisulphite solution followed by stirring with sodium carbonate solution. Dichloromethane was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous sodium sulphate and then the solvent was removed under reduced pressure to yield a crude product. Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 17-25% acetone in hexane to afford the desired product. Preparation of compound of Formula VI Compound of Formula VI can be prepared by three different methods.
Method A
To a solution of compound of Formula V (1 equiv) in acetonitrile was added solid sodium hydrogen carbonate (5 equiv) and ethyl iodide (6 equiv) under argon at an ambient temperature and stirred and the reaction was quenched by the addition of water. 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. Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-15% acetone in hexane to afford the desired product.
Method B
The compound of Formula V (1 equiv) in acetone and methanol was stirred at an ambient temperature. A solution of acetic acid was added and stirred and to it was added sodium cyanoborohydride (2 equiv) and stirred. Solvent was evaporated under reduced pressure and the crude product was extracted with ethyl acetate. Ethyl acetate layer was combined and washed with water, brine, and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the crude product was done by silica gel colunm chromatography (thoroughly neutralized with triethylamine) using 10-20% acetone in hexane to afford the desired product.
Method C
To a solution of compound of Formula V (1 equiv) in methanol was added (1-ethoxycyclopropoxy) trimethylsilane (3 equiv) followed by glacial acetic acid (10 equiv) at an ambient temperature and stirred. The reaction mixture was cooled and was added sodium cyanoborohydride (5 equiv). Then the reaction mixture was stirred and refluxed. Methanol was evaporated under reduced pressure, and water was added. Organic layer was extracted with ethyl acetate. Ethyl acetate layer was combined and washed with water, brine, and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-20% acetone in hexane to afford the desired product. Preparation of compound of Formula VII
To a solution of compound of Formula VI (1 equiv) in dichloromethane was added triphosgene (1.5 equiv). To it pyridine was added (15 equiv) slowly. After complete addition, reaction mixture was stirred; reaction was quenched by addition of ice-cold water. Reaction mixture was diluted with dichloromethane and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product.
Preparation of compound of Formula VIE
To a solution of compound of Formula VII (1 equiv) in dimethylformamide was added tetramethyl guanidine (2.2 equiv) and heated. Reaction mixture was cooled to an ambient temperature. Organic layer was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the desired product.
Preparation of compound of Formula DC
To a solution of compound of Formula VIII (1 equiv) in dichloromethane Dess-Martine Periodinane (2.5 equiv) was added and refluxed. Reaction was cooled to an ambient temperature and quenched by addition of saturated aqueous potassium carbonate solution followed by saturated sodium thiosulphate solution and stirred. Aqueous layer was separated and extracted with dichloromethane. Dichloromethane 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 X
To a solution of compound of Formula DC (1 equiv) in dimethylformamide: tetrahydrofuran (3:2) N,N'-carbonyl diimidazol (3 equiv) at an ambient temperature was added. It was cooled, sodium hydride (3 equiv) was added in portions and was stirred. The reaction mixture was quenched by addition of water. It was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product. Preparation of compound of Formula XI
Compound of Formula XI can be prepared by two different methods. Method A
The compound of Formula X (1 equiv) and R-W-NH2 (2 equiv) were taken in water in acetonitrile and heated, reaction mixture was cooled to attain an ambient temperature and acetonitrile was removed under reduced pressure. The resulting residue was taken in ethyl acetate and washed with water, brine, dried over anhydrous sodium sulphate, and filtered. The
filtrate was collected and concentrated under reduced pressure. Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 25-30% acetone in hexane to afford the desired product.
Method B
The compound of Formula X (1 equiv) and R-W-NH2 (2 equiv) were taken in dimethylformamide and heated. Reaction mixture was cooled to an ambient temperature; dimethylformamide was evaporated under reduced pressure. The resulting crude product was taken in ethyl acetate and washed with water, brine, and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 25-30% acetone in hexane to afford the desired product. Preparation of compound of Formula Xn Method A
To a solution of compound of Formula XI (1 equiv) in dimethylformamide was added sodium hydride (1.5 equiv) in portions. Then added N-fluorobenzene sulfonimide (1.2 equiv). Reaction was quenched by addition of water and extracted with ethyl acetate. Organic layer was washed with water followed by brine, dried over anhyrdous sodium sulphate and concentrated under reduced pressure.
Method-B
To a solution of compound of Formula XI (1 equiv) in tetrahydrofiiran was added potassium(tert)butoxide (1.5 equiv) at -15 °C, stirred for 20 min. Then added N-fluorobenzene sulfonimide (1.2 equiv) in tetrahydrofiiran. Reaction mixture was stirred at -15 °C for 3h, quenched by addition of water and extracted with ethyl acetate. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Preparation of compound of Formula Xm
The compound of Formula XII (560 mg, 0.6 mmol) was taken in methanol and refluxed. Reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure. Purification of the solid mass was done over a silica gel column
(thoroughly neutralized with triethylamine) using 20-40% acetone in hexane or 2-6% methanol in dichloromethane to afford the desired product.
Scheme 11
Preparation of compound of Formula XIV
To a solution of compound of Formula PV (1 equiv) in dichloromethane was added triphosgene (1.5 equiv). To it was added pyridine (15 equiv) slowly, exothermic reaction was observed. After complete addition, reaction mixture was stirred for about 3-4 hours at (fC. The reaction was quenched by addition of ice-cold water. Reaction mixture was diluted with dichloromethane and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product.
Preparation of compound of Formula XV
To a solution of compound of Formula XIV (1 equiv) in dimethylformamide was added tetramethyl guanidine (2.2 equiv) and heated at 65-70 °C for about 3-4 hours. Reaction mixture was cooled to an ambient temperature. Organic layer was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the desired product. Preparation of compound of Formula XVI
To a solution of compound of Formula XV (1 equiv) in dichloromethane was added Dess-Martine Periodinane (2.5 equiv) and stirred at 30 °C for about 1 hour. Reaction was quenched by addition of saturated aqueous potassium carbonate solution followed by saturated sodium thiosulphate solution and stirred. Aqueous layer was separated and extracted with dichloromethane. Dichloromethane 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 XVn
To a solution of compound of Formula XVI (1 equiv) in dry acetonitrile: dichloromethane (2:1) was added N-iodosuccinimide (2 equiv) and the reaction mixture was allowed to attain an ambient temperature and stirred for about 3-4 hours. Then the reaction
mixture was stirred with a sodium bisulphite solution followed by stirring with sodium carbonate
solution. Dichloromethane was evaporated under reduced pressure. The aqueous layer was
extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous
sodium sulphate and then the solvent was removed under reduced pressure to yield a crude
product.
Preparation of compound of Formula IX
To a solution of compound of Formula XVn (1 equiv) in acetonitrile was added solid sodium hydrogen carbonate (5 equiv) and ethyl iodide (6 equiv) under argon at an ambient temperature and stirred for about 18-20 hours. Reaction was quenched by the addition of water. 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. Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-15% acetone in hexane to afford the desired product. Preparation of compound of Formula XVm
Method-A
To a solution of compound of Formula DC (1 equiv) in dimethylformamide was added sodium hydride (1.5 equiv) in portions at 0 °C, stirred for about 15 min. Then N-fluorobenzene sulfonimide (1.2 equiv) was added. Reaction mixture was stirred at 0 °C for about 3 hour. Reaction was quenched by addition of water and extracted with ethyl acetate. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
Method- B
To a solution of compound of Formula IX (1 equiv) in tetrahydrofuran was added potassium tert. butoxide at -15 °C, stirred for about 20 min. Then N-fluorobenzene sulfonimide (1.2 equiv) in tetrahydrofuran was added. Reaction mixture was stirred at -15 °C for about 2 hours, quenched by addition of water and extracted with ethyl acetate. Organic layer was washed
with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
Preparation of compound of Formula XIX
To a solution of compound of Formula XVm (1 equiv) in dimethylformamide: tetrahydrofuran (3:2) was added N, N'-carbonyl diimidazol (3 equiv) at an ambient temperature. It was cooled to 0 °C and sodium hydride (3 equiv) in portions was added and was stirred for about 30 min. Reaction was quenched by addition of water. This was 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 Xn
The compound of Formula XDC (1 equiv) and R-W-NH2 (3 equiv) were taken in 10% water in acetonitrile and heated to 65-70 °C for about 14 hours. Reaction mixture was cooled to attain an ambient temperature; acetonitrile-water was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (thoroughly neutralized with triethylamine) using 25-30% acetone in hexane to afford the desired product. Preparation of compound of Formula XIII
The compound of Formula XII was taken in methanol and refluxed for about 12 hours. Reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure. Purification of the solid mass was done over a silica gel column using 2-6% methanol in dichloromethane. Scheme III
Preparation of compound of Formula XX
Method-A
To a solution of compound of Formula XVI (1 equiv) in dimethylformamide was added sodium hydride (1.5 equiv) in portions at 0 °C, stirred for about 15 min. Then added N-fluorobenzene sulfonimide (1.2 equiv). Reaction mixture was stirred at 0 °C for about 4 hours.
Reaction was quenched by addition of water and extracted with ethyl acetate. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
Method-B
To a solution of compound of Formula XVI (1 equiv) in tetrahydrofuran was added potassium tert. butoxide (1.5 equiv) at -15 °C, stirred for about 20 min. Then added N-fluorobenzene sulfonimide (1.2 equiv) in tetrahydrofuran. Reaction mixture was stirred at -15 "^C for about 3 hours, quenched by addition of water and extracted with ethyl acetate. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
Preparation of compound of formula XXI
To a solution of compound of Formula XX (1 equiv) in dimethylformamide: tetrahydrofuran (3:2) was added N, N'-carbonyl diimidazol (3 equiv) at an ambient temperature. It was cooled to 0 °C and sodium hydride (3 equiv) in portions was added and was stirred for about 30 min. Reaction was quenched by addition of water. This was 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 XXn
The compound of Formula XXI (1 equiv) and R-W-NH2 (2 equiv) were taken in 10%water in acetonitrile and heated to 65-70 °C for about 14 hours. Reaction mixture was cooled to attain an ambient temperature; acetonitrile-water was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (thoroughly neutralized with triethylamine) using 25-30% acetone in hexane to afford the desired product. Preparation of compound of Formula XXni
The compound of Formula XXn (560 mg, 0.6 mmol) was taken in methanol and refluxed. Reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure.
Preparation of compound of Formula XXFV
To a solution of compound of Formula XXIII (1 equiv) in dry acetonitrile was added N-iodosuccinimide (2 equiv) and the reaction mixture was allowed to attain an ambient temperature and stirred for 4h. Then the reaction mixture was stirred with a sodium bisulphite solution followed by stirring with sodium carbonate solution. The aqueous layer was extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous sodium sulphate and then the solvent was removed under reduced pressure to yield a crude product. Preparation of compound of Formula XrH
To a solution of compound of Formula XXFV (1 equiv) in acetonitrile was added solid sodium hydrogen carbonate (5 equiv) and ethyl iodide (6 equiv) under argon at an ambient temperature and stirred for about 20 hours. Reaction was quenched by the addition of water. 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. Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 30-35% acetone in hexane to afford the desired product.
Scheme IV
Preparation of compound of formula XXV
The compound of Formula XX was taken in methanol and refluxed. Reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure. The crude product was purified by column chromatography.
Preparation of compound of formula XXVI
To a solution of compound of Formula XXV (1 equiv) in dry acetonitrile was added N-iodosuccinimide (2 equiv) and the reaction mixture was allowed to attain an ambient temperature and stirred for about 4 hours. Then the reaction mixture was stirred with a sodium bisulphite solution followed by stirring with sodium carbonate solution. The aqueous layer was extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous
sodium sulphate and then the solvent was removed under reduced pressure to yield a crude product.
Preparation of compound of formula XXVn
To a solution of compound of Formula XXVI (1 equiv) in acetonitrile was added solid sodium hydrogen carbonate (5 equiv) and ethyl iodide (6 equiv) under argon at an ambient temperature and stirred for about 20 hours. Reaction was quenched by the addition of water. 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. Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 20-25% acetone in hexane to afford the desired product.
Preparation of compound of Formula XVni
To a solution of compound of Formula XXVn (1 equiv) in acetone was added potassium carbonate (2 equiv) and it was stirred for about 5 min. Then to it was added acetic anhydride (5 equiv) stirred for about 24 hours at ambient temperature. Reaction mixture was poured into chilled aqueous potassium carbonate solution and extracted with dichloromethane. Dichloromethane layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated.
Preparation of compound of formula XIX
To a solution of compound of Formula XVin (1 equiv) in dimethylformamide: tetrahydrofuran (3:2) was added N, N'-carbonyl diimidazol (3 equiv) at an ambient temperature. It was cooled to 0 °C and sodium hydride (3 equiv) was added in portions and it was stirred for about 30 min. Reaction was quenched by addition of water. This was 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 Xn
The compound of Formula XIX (1 equiv) and R-W-NH2 (2 equiv) were taken in 10%water in acetonitrile and heated to 65-70 °C for about 14 hours. Reaction mixture was cooled to attain an ambient temperature; acetonitrile-water was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (thoroughly neutralized with triethylamine) using 25-30% acetone in hexane to afford the desired product. Preparation of compound of Formula Xin
The compound of Formula XII was taken in methanol and refluxed. Reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure. Purification of the solid mass was done over a silica gel column using 2-6% methanol in dichloromethane.
The following compounds were prepared following the above general procedures
Compound No.l: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-imino]erythromycin A MS (+ ion mode): m/z 753.6 [M+1]
Compound No.2: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-iminojerythromycin A MS (+ ion mode): m/z 818.4 [M+1]
Compound No.3: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((4-(3H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 818.3 [M+1]
Compound No. 4:2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 817.6 [M+1]
Compound No. 5:2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxyca^bonyl-((4-imidazol-l-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 767.6 [M+1]
Compound No. 6: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-
imino] erythromycin A
MS (+ ion mode): m/z 765.6 [M+1]
Compound No.7: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-imino] erythromycin A MS (+ion mode): m/z 767.5 [M+1]
Compound No. 8: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-propyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-
imino] erythromycin A
MS (+ ion mode): m/z 767.6 [M+1]
Compound No. 9: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-propyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ion mode): m/z 831.3 [M+1]
Compound No. 10: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo-(2,3-b)pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 829.4 [M+1]
Compound No. 11: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo-(2,3-b)pyridin-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 831.6 [M+1]
Compound No. 12: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 831.4 [M+1]
Compound No.13: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 829.7 [M+1]
Compound No.l4: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-n-propyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-imidazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 781.5 [M+1]
Compound No. 15: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-((4-pyrrolo-(2,3-b)pyridin-1-yl)-butyl)-imino] erythromycin A MS (+ion mode): m/z 817.6 [M+1]
Compound 16: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 832.9 [M+1]
Compound No.l7: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxyca^bonyl-((4-purin-9-yl)-butyl)-imino]eryth^omycin A MS (+ ion mode): m/z 820.0 [M+1]
Compound No.18: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 830.4 [M+1]
Compound No.l9: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-(4-(4-pyridin-3-yl-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ion mode): m/z 844.55 [M+1]
Compound No. 20: 2a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N'-methyl-N'-quinolin-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A MS (+ ion mode): m/z 843.90 [M+1]
Compound No. 21: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-methyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A MS (+ ion mode): m/z 794.00 [M+1]
Compound No. 22: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-methyl-N-pyridine-4-ylmethyl)-2-aminoethyl)-imino] erythromycin A MS (+ ion mode): m/z 794.00 [M+1]
Compound No. 23: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-methyl-N'-pyridine-2-ylmethyl)-2-aminoethyl)-imino]erythromycin A MS (+ ion mode): m/z 794.01 [M+1]
Compound No. 24: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-methyl-N'-pyridine-2-ylmethyl)-2-aminoethyl)-imino]erythromycin A MS (+ ion mode): m/z 805.58 [M+1]
Compound No. 25: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-methyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A MS (+ ion mode): m/z 805.45 [M+1]
Compound No. 26: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-methyl-N'-pyridine-4-ylmethyl)-2-aminoethyl)-imino] erythromycin A MS (+ ion mode): m/z 805.40 [M+1]
Compound No.27: 2-a-Fluoro-5-0-(3'-N-desmethyI-3'-N-alIyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((N'-methyl-N'-quinoline-4-ylmethyl)-2-aminoethyl)-imino]erythromycin A MS (+ ion mode): m/z 855.59 [M+1]
Compound No. 28: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-pyridine-3-ylmethyl)-2-aminoethyl)-
imino]erythromycin A
MS (+ ion mode): m/z 779.71 [M+1]
Compound No.29:2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-
6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-acetyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-
imino]erythromycin A
MS (+ ion mode): m/z 833.78 [M+1]
Compound No.30: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino]erythromycin A MS (+ ion mode): m/z 791.73 [M+1
Compound No. 31: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N'-acetyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A MS (+ ion mode): m/z 821.76 [M+1]
Compound No. 32: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N',N'-di-pyridine-3-ylmethyl)-2-aminoethyl)-imino]er3'thromycin A MS (+ ion mode): m/z 870.54 [M+1]
Compound No. 33: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyI-3-oxo-12,ll-[oxycarbonyI-((N',N'-di-pyridine-3-yImethyl)-2-aminoethyl)-imino]erythromycin A MS (+ ion mode): m/z 882.69 [M+1]
Compound No. 34: 2-a-FIuoro-5-0-(3'-N-desmethyl-3'-N-aIlyl)-ll,I2-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-quino]in-3-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 840.7 [M+1]
Compound No. 35: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-quinolin-8-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 829[M+1]
Compound No.36: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((4-pyridin-2-yl)-butyl)-iminojerythromycin A MS (+ ion mode): m/z 778 [M+1]
Compound No. 37: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyridin-3-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 778 [M+1]
Compound No. 38: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyridin-4-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 778 [M+1]
Compound No. 39: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-pyridin-2-yl)-butyl)-
imino]erythromycin A
MS (+ ion mode): m/z 789 [M+1]
Compound No. 40: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decIadinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyridin-4-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 789 [M+1]
Compound No.41: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3 -oxo-12,11 -[oxycarbonyl-((4-pyridin-3 -yl)-pentyl)-
imino] erythromycin A
MS (+ ion mode): m/z 804.77 [M+1]
Compound No. 42: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyridin-3-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 790.50 [M+1]
Compound No. 43: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-indol-l-yl)-butyl)-imino]erythromycin
A
MS (+ ion mode): m/z 816.8 [M+1]
Compound No. 44: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 843.9 [M+1]
Compound No. 45: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-nitro)-indol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ion mode): m/z 861.8 [M+1]
Compound No. 46: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3 -0X0-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-c]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 819.1 [M+1]
Compound No. 47: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-2-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 818.9 [M+1]
Compound No. 48: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-c]pyridin-3-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 819 [M+1]
Compound No. 49: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 855.8 [M+1]
Compound No. 50: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 830.7 [M+1]
Compound No. 51: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-benzotriazol-2-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 830.9 [M+1]
Compound No. 52: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imdazo[4,5-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 830.9 [M+1]
Compound No. 53: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-indol-1 -yl)-butyl)-imino] erythromycin
A
MS (+ ion mode): m/z 828.9 [M+1]
Compound No. 54: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 830.9 [M+1]
Compound No. 55: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosy]-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 829.9 [M+1]
Compound No. 56: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-
butyl)-imino] erythromycin A
MS (+ ion mode): m/z 830.9 [M+1]
Compound No. 57: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 858.1 [M+1]
Compound No. 58: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-benzotriazol-2-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 832.8 [M+1]
Compound No. 59: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-indol-1 -yl)-butyl)-imino] erythromycin
A
MS (+ ion mode): m/z 830.9 [M+1]
Compound No. 60: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-
butyl)-imino] erythromycin A
MS (+ ion mode): m/z 832.9 [M+1]
Compound No. 61: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-nitro)-indol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 875.38 [M+1]
Compound No. 62: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-nitro)-indol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 873.54 [M+1]
Compound No.63: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-fluoro)-indol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 834.57 [M+1]
Compound No. 64: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 818.9 [M+1]
Compound No. 65: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3 -0X0-12,11 -[oxycarbonyl-((4-(2-methyl)-benzoimidazoI-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 831.57 [M+1]
Compound No. 66: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-ethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 845.58 [M+1]
Compound No. 67: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3 -0X0-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 832.54 [M+1]
Compound No. 68: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-ethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 857.56 [M+1]
Compound No.69: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-0-
decladi^osyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(4-py^idin-3-yl-imidazol)-l-yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 856.64 [M+1]
Compound No. 70: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyI-3 -0X0-12,11 -[oxycarbonyl-((4-(2-methyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 843.53 [M+1]
Compound No. 71: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 829.59 [M+1]
Compound No. 72: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 830.6 [M+1]
Compound No. 73: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-
butyl)-imino] erythromycin A
MS (+ ion mode): m/z 836.65 [M+1]
Compound No. 74: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-nitro)-indol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 879.5 [M+1]
Compound No. 75: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyI)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-pyridin-3-ylmethyl)-benzoimidazol-l-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 920.74 [M+1]
Compound No. 76: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-pyridin-3-ylmethyl)-benzoimidazol-l-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 908.71 [M+1]
Compound No. 77: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 855.6 [M+1]
Compound No. 78: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyI-3-oxo-12,11-[oxycarbonyl-((4-(5-fluoro)-indol-1-yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 846.57 [M+1]
Compound No. 79: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5,6-dimethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 857.89 [M+1]
Compound No. 80: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5,6-dimethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 845.8 [M+1]
Compound No. 81: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-c]pyridin-3-yl)-
butyl)-imino] erythromycin A
MS (+ ion mode): m/z 831.7 [M+1]
Compound No. 82: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(2-methyl)-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 844.67 [M+1]
Compound No. 83: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(2-methyl)-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 832.68 [M+1]
Compound No. 84: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-c]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 830.78 [M+1]
Compound No. 85: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3 -0X0-12,11 -[oxycarbonyl-((9-(4-amino-butyl)-9H-purin-6-yl)-imino] erythromycin A MS (+ ion mode): m/z 834.78 [M+1]
Compound No.86: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 843.8 [M+1]
Compound No. 87: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 831.82 [M+1]
Compound No. 88: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl methyl)-! 1,12-dideoxy-
3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-
butyl)-imino] erythromycin A
MS (+ ion mode): m/z 844.85 [M+1]
Compound No. 89: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl methyl)-! 1,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino]erytliromycin A MS (+ ion mode): m/z 843.86 [M+1]
Compound No. 90: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl methyl)-! 1,12-dideoxy-3-0-decladinosyI-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 843.8 [M+1]
Compound No.91: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methy!-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 835.83 [M+1]
Compound No.92: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ ion mode): m/z 836.74 [M+1]
Compound No. 93: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3 -0X0-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino]erytliromycin A MS (+ ion mode): m/z 835.77 [M+1]
Compound No. 94: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 861.8 [M+1]
Compound No. 95: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-trifluoromethyI)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 885.75 [M+1]
Compound No. 96: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-!!,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4,5 -diphenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 919.15 [M+1]
Compound No.97: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-! !,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-! 2,11 -[oxycarbonyl-((4-(4,5-diphenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 931.85 [M+1]
Compound No. 98: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-l!,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3 -0X0-12,1! -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 855.75 [M+1]
Compound No. 99: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl methyl)-! 1,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 869.85 [M+1]
Compound No. 100: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl methyl)-! 1,12-dideoxy-
3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-benzotriazol-!-yl)-butyl)-
imino]erytliromycin A
MS (+ ion mode): m/z 844.8 [M+1]
Compound No. 101: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl methyl)-! 1,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 870.82 [M+1]
Compound No. 102: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,1! -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 831.78 [M+1]
Compound No. 103: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-l!,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3 -0X0-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-! -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 857.83 [M+1]
Compound No. 104: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-!l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 832.77 [M+1]
Compound No.l05: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-l l,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 832.77 [M+1]
Compound No. 106: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3,5-diphenyl)-pyrazol-1 -yl)-butyl)-iminojerythromycin A MS (+ ion mode): m/z 931.85 [M+1]
Compound No. 107: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridn-3-yl)-imidazol-1 -yl)-butyl)-iminojerythromycin A MS (+ ion mode): m/z 862.69 [M+1]
Compound No. 108: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 834 [M+1]
Compound No. 109: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3,5-diphenyl)-pyrazol-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 919.85 [M+1]
Compound No. 110: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl methyl)-ll,12-dideoxy-
3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(lH)-imidazo[4,5-b]pyridin-l-yl)-
butyl)-imino] erythromycin A
MS (+ ion mode): m/z 844.8 [M+1]
Compound No. Ill: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazo)-1 -yl)-butyl)-imino] erythromycin A MS (+ ion mode): m/z 858.64 [M+1]
Compound No.l 12: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((4-(4-(2,4-difluoro)-phenyl)-imidazol-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 897.6 [M+1]
Compound No. 113: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-ethyl)-11,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(2,4-difluoro)-phenyl)-imidazol)-1 -yl)-butyl)-imino]erythromycin A MS (+ ion mode): m/z 879.62 [M+1]
Compound No. 114: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-allyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(2,4-difluoro)-phenyl)-imidazol)-1 -
yl)-butyl)-imino]erythromycin A
MS (+ionmode):m/z 891.65[M+1]
Compound No. 115: 2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl~(4-((4-furan-2-yl)-imidazol-1 -yl)-butyl)-
imino] erythromycin A
MS (+ionmode):m/z 833.56[M+1]
Microbiological activity
Compounds disclosed herein displayed 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 CO2 incubation (5% CO2) at 37 °C for about 18-24 hours. Three to four
well isolated colonies were taken and saline suspensions were prepared in sterile densimat tubes.
The turbidity of the culture was adjusted to 0.5-0.7 Mc Farland standard (1.5 x 10^ CFU/ml).
The cultures were diluted 10 fold in saline to get inoculum size of approximately 1-2 x 10^
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 µg/ml - 16 µg/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 [il 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 10|ag 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.
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, enantiomers, diastereomers or polymorphs wherein R' represents —hydrogen
—hydroxyl protecting group R"and R' are independently selected from
— alkyl (with theprovisio that R andRsimultaneously are not methyl)
—alkenyl
—alkynyl —cycloalkyl —aryl
—heterocycle —aralkyl
—(heterocycle)alkyl —C0R'\ wherein R" represents o hydrogen o alkyl o aralkyl
W represents
— alkenyl
G(CH2)qJ- wherein q represents an integer 2 to 6 and G represents
o no atom o -CO o -CS o -SO2
- -CR'R'°
- -NR-
- -SO2
wherein R and R"' are selected from o hydrogen o alkyl
and J represents
— no atom
CRR*° ,wherein R and R'° are the same as defined earher.
— -N-(CH ) - ' wherein m represents an integer 1 to 6 and R represents
o hydrogen
o alkyl
o alkylene
o alkynyl
o COR, wherein R represents alkyl,aryl or heterocycle
Q Q
o -(CH2)m-R , wherein m is the same as defined earlier and R represents alkyl,aryl or heterocycle R represents —aryl
—heterocycle R"* represents —alkyl —alkenyl —alkynyl R' represents —alkyl
— -(CH2)r-U-V
wherein r represents an integer 1 to 4
U represents
o alkenyl
o alkynyl
V represents
o no atom
o alkyl
o aryl
o heterocycle
Y represents
—halogen
—cyano
—alkyl
Z represents
—oxygen
—sulphur
— NOR' ' wherein R' ' is the same as defined earlier.
2. A compound according to claim 1 wherein R is optionally substituted mono heterocycle wherein the optional substituent is aryl.
3. A compound according to claim 1 wherein R is optionally substituted monoheterocycle wherein the optional substituent is phenyl.
4. A compound according to claim 1 wherein R is optionally substituted monoheterocycle wherein the optional substituent is difluorophenyl.
5. A compound according to claim 1 wherein R is optionally substituted monoheterocycle wherein the optional substituent is heterocycle.
6. A compound according to claim 1 wherein R is optionally substituted monoheterocycle wherein the optional substituent is pyridine.
7. A compound according to claim 1 wherein R is optionally substituted monoheterocycle wherein the optional substituent is furan.
8. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is nitro.
9. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is halogen.
10. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is fluoro.
11. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is alkyl.
12. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is methyl.
13. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is ethyl.
14. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is trifluoromethyl.
15. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is heterocyclylalkyl.
16. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is pyridyl methyl.
17. A compound according to claim 1 wherein R is optionally substituted bicyclic heterocycle wherein the optional substituent is amino.
18. A compound according to claim 1 wherein R is 2-pyridyl.
19. A compound according to claim 1 wherein R is 3-pyridyl.
20. A compound according to claim 1 wherein R is 4-pyridyl.
21. A compound according to claim 1 wherein R is 3,5-diphenylpyrazol-l-yl.
22. A compound according to claim 1 wherein R is imidazolyl.
23. A compound according to claim 1 wherein R is 4-phenyl-l-imidazolyl.
24. A compound according to claim 1 wherein R is 2-phenyl-l-imidazolyl.
25. A compound according to claim 1 wherein R is 4-pyridin-3-yl-imidazolyl.
26. A compound according to claim 1 wherein R is (4,5-diphenyl)imidazolyl.
27. A compound according to claim 1 wherein R is (2,4-difluoro)phenylimidazolyl.
28. A compound according to claim 1 wherein R is quinolin-4-yl.
29. A compound according to claim 1 wherein R is quinolin-3-yl.
30. A compound according to claim 1 wherein R is quinolin-8-yl.
31. A compound according to claim 1 wherein R is beazoimidazolyl.
32. A compound according to claim 1 wherein R is (2-methyl) benzoimidazolyl.
33. A compound according to claim 1 wherein R is (3-ethyl) beazoimidazolyl.
34. A compound according to claim 1 wherein R is 5,6-dimethylbenzoimidazolyl.
35. A compound according to claim 1 wherein R is 2-(trifluoromethyl) beazoimidazolyl.
36. A compound according to claim 1 wherein R is (2-pyridine-3-yl-methyl) benzoimidazolyl.
37. A compound according to claim 1 wherein R is indol-1-yl.
38. A compound according to claim 1 wherein R is 5-nitro indolyl.
39. A compound according to claim 1 wherein R is 5-fluoro indolyl.
40. A compound according to claim 1 wherein R is (IH)- imidazo [4,5-c] pyridin -1-yl.
41. A compound according to claim 1 wherein R is (3H)- imidazo [4,5-c] pyridin-3-yl.
42. A compound according to claim 1 wherein R is (3H)- imidazo [4,5-b] pyridin -3-yl.
43. A compound according to claim 1 wherein R is (IH)- imidazo [4,5-b] pyridin-1-yl.
44. A compound according to claim 1 wherein R is pyrrolo [2,3-b] pyridin-1-yl.
45. A compound according to claim 1 wherein R is (2-methyl)- (3H)-[imidazo-4,5-b] pyridin-3-yl.
46. A compound according to claim 1 wherein R is 4-amino-9H-purin-6-yl.
47. A compound according to claim 1 wherein R is 2-benzotriazolyl.
48. A compound according to claim 1 wherein R is 1-benzotriazolyl.
49. A compound according to claim 1 wherein R is ((4-furan-2-yl)-imidazol-l-yl).
50. A compound according to claim 1 wherein R and R are respectively, methyl and alkyl.
51. A compound according to claim 1 wherein R and R are respectively, methyl and ethyl.
52. A compound according to claim 1 wherein R and R are respectively, methyl and n-propyl.
53. A compound according to claim 1 wherein R and R are respectively, methyl and fluoroethyl.
54. A compound according to claim 1 wherein R and R are respectively, methyl and isopropyl.
55. A compound according to claim 1 wherein R and R are respectively, methyl and cycloalkyl.
56. A compound according to claim 1 wherein R and R are respectively, methyl and cyclopropyl.
57. A compound according to claim 1 wherein R and R are respectively, methyl and substituted alkyl wherein the substituent is cycloalkyl.
58. A compound according to claim 1 wherein R and R are respectively, methyl and cyclopropylmethyl.
59. A compound according to claim 1 wherein R and R are respectively, methyl and -COR" ,wherein R" is the same as defined for Formula I.
60. A compound according to claim 1 wherein R and R are respectively, methyl and acetyl.
61. A compound according to claim 1 wherein R and R are respectively, methyl and alkenyl.
62. A compound according to claim 1 wherein R and R are respectively, methyl and allyl.
63. A compound according to claim 1 wherein W represents -G(CH2)qJ-, wherein G = no atom, q=4 and J= no atom.
64. A compound according to claim 1 wherein W represents -G(CH2)qJ-, wherein G = no atom, q=2 and J= -NiCH^jm- , wherein R and m are the same as defined before.
65. A compound according to claim 1 wherein W represents -G (CH2)qJ-, wherein
= no atom, q=2 and J= -N-(CH2)m- , wherein R =H and m=l.
66. A compound according to claim 1 wherein W represents -G(CH2)qJ-, wherein G
= no atom, q=2 and J= -N-(CH2)m- , wherein R =alkyl and m=l.
67. A compound according to claim 1 wherein W represents -G(CH2)qJ-, wherein G
= no atom, q=2 and J= -N-ccH^jm-, wherein R =methyl and m=l.
68. A compound according to claim 1 wherein W represents -G(CH2)qJ-, wherein G= no atom, q=2 and J= -NiCHjjm-, wherein R ==C0R , R is the same as defined earlier and m=l.
69. A compound according to claim 1 wherein W represents -G(CH2)qJ- , wherein G = no atom, q=2 and J= -NiCHjm- , wherein R =C0R R is alkyl and m=l.
70. A compound according to claim 1 wherein W represents -G(CH2)qJ-, wherein G
= no atom, q=2 and J=, wherein R =COR, R is methyl and m=l.
71. A compound according to claim 1 wherein W represents -G(CH2)qJ-, wherein G
= no atom, q=2 and J= -NiCHjm- , wherein R =-(CH2)mR , R is heterocyclyl andm=l.
72. A compound according to claim 1 wherein W represents -G(CH2)qJ-, wherein G = no atom, q=2 and J= -N-CCHJ)™- , wherein R =-(CH2)mR, R is pyridyl and m=l.
73. A compound according to claim 1 wherein W represents -CR'R wherein R and R'° are the same as defined earlier.
74. A compound which is:
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino] erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-imidazol-1 -yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((3-imidazol-l-yl)-propyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-propyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((3-imidazol-1 -yl)-propyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-propyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino] erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-11,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo-(2,3-b)pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo-(2,3-b)pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino] erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 - [oxycarbonyl-((4-benzoimidazol-1-yl)-butyl)-imino] erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-n-propyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-imidazol-l-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo-(2,3-b)pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-purin-9-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3H)-imidazo(4,5-b)-pyridin-1 -yl)-butyl)-iminojerythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-pyridin-3-yl-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-methyl-N'-quinolin-4-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N'-methyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N'-methyl-N-pyridine-4-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-methyl-N'-pyridine-2-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N'-methyl-N'-pyridine-2-ylmethyl)-2-aminoethyl)-imino]e^ythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-methyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N'-methyl-N'-pyridine-4-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N'-methyl-N'-quinoline-4-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyI)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-acetyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5 -0-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((N'-acetyl-N'-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0- (3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N',N'-di-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((N',N'-di-pyridine-3-ylmethyl)-2-aminoethyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-quinolin-3-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-quinolin-8-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyridin-2-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyridin-3-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyridin-4-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyridin-2-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyridin-4-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0- (3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-
methyl-3-oxo-12,ll-[oxycarbonyl-((4-pyridin-3-yl)-pentyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,11 -[oxycarbonyl-((4-pyridin-3-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-indol-l-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-nitro)-indol-1 -yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-c]pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((4-benzotriazol-2-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-((4-(3H)-imidazo[4,5-c]pyridin-3-yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-11,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-11,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino] erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-benzotriazol-2-yl)-butyl)-imino]erythromycin
A,
-2-a-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-cyclopropyl)-11,12-dideoxy-3 -O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imdazo[4,5-b]pyridin-1 -yl)-butyl)-iminojerythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl)-11,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-indol-1 -yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-aIIyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-iniino] erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-2-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyI)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-indol-1 -yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-nitro)-indol-1 -yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5 -0-(3 '-N-desmethyl-3 '-N-cyclopropyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(5-nitro)-indol-l-yl)-butyl)-imino]erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-fluoro)-indol-1 -yl)-butyl)-imino]erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-iniino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-methyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-ethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-isopropyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-ethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl-imidazol)-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-methyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3 -oxo-12,11- [oxycarbonyl-((4-( 1 H)-imidazo [4,5 -bjpyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-nitro)-indol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-pyridin-3-ylmethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-pyridin-3-ylmethyl)-benzoimidazol-1 -yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-alIyl)-ll,12-dideoxy-3-0-decladinosyI-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5-fluoro)-indol-1 -yl)-butyl)-imino] erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3 -0X0-12,11 -[oxycarbonyl-((4-(5,6-dimethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(5,6-dimethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyI-((4-(3H)-imidazo[4,5-c]pyridin-3-yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(2-methyl)-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((4-(2-methyl)-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-c]pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((9-(4-amino-butyl)-9H-purin-6-yl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-phenyl)-iniidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino] erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3 '-N-desmethyl-3 -N-cyclopropylmethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3 -0X0-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino] erythromycin
A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyI-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(2-trifluoromethyl)-benzoimidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4,5-diphenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4,5-diphenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-l 1,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo- 12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-benzotriazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropylmethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazol-1 -yl)-butyl)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-pyrrolo[2,3-b]pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( lH)-imidazo[4,5-b]pyridin-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3H)-imidazo[4,5-b]pyridin-3-yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3,5-diphenyl)-pyrazol-1 -y])-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridn-3-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1 -yl)-butyl)-iminojerythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3,5-diphenyl)-pyrazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-cyclopropyl methyl)-11,12-dideoxy-3-0-
decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-((4-( 1 H)-imidazo[4,5-b]pyridin-1-yl)-butyI)-imino]erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-acetyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl)-imidazo)-1 -yl)-butyl)-iminojerythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-fluoroethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(2,4-difluoro)-phenyl)-imidazol-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(2,4-difluoro)-phenyl)-imidazol)-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-2-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(2,4-difluoro)-phenyl)-imidazol)-1 -yl)-butyl)-imino] erythromycin A,
-2-a-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl~(4-((4-furan-2-yl)-imidazol-1 -yl)-butyl)-imino] erythromycin A.
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, nantiomers, diastereomers or polymorphs.
75. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the preceeding claims togather with pharmaceutically acceptable carrier, excipients, or diluents.
76. 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 to 74.
77. 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 75.
78. The method according to claim 76 or 77 wherein the said condition is selected from the group comprising of community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or bone and joint infections, mastitis, catether infection, foreign body, prosthesis infections and peptic ulcer disease.
79. The method according to claim 76 or 77 wherein the said bacterium is gram positive, gram negative or anaerobic bacteria.
80. The method according to claim 79 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.
81. The method according to claim 80 wherein the bacterium is cocci.
82. The method according to claim 81 wherein the cocci is drug resistant.
83. A process for preparing a compound of Formula XIII, , as shown in Scheme I of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, wherein
R represents
— alkyl {with theprovisio that R is not methyl)
—alkenyl
—alkynyl
—cycloalkyl
—aryl
—heterocycle
—aralkyl
—(heterocycle)alkyl
—COR'' wherein R" represents
o hydrogen
o alkyl
o aralkyl W represents
- alkenyl
G(CH2)qJ- wherein q represents an integer 2 to 6 and G represents
o no atom o -CO o -CS o -SO2
- -CR'R'°
- -NR-
- -SO2
wherein R and R*' are selected from
o hydrogen
o alkyl and J represents
- no atom
-CRR , wherein R and R'° are the same as defined earher.
I , wherein m represents an integer 1 to 6 and R represents
-N-(CH2)m-
o hydrogen
o alkyl
o alkylene
o alkynyl
o COR, wherein R represents alkyl,aryl or heterocycle
o -(CH2)ra-R , wherein m is the same as defined earlier and R represents alkyl,aryl or heterocycle R represents —aryl
—heterocycle, which comprises:
hydrolyzing clarithromycin of Formula II to give a compound of Formula HI, which on protection with a reagent of Formula R'IO or RX (wherein X is halogen) gives a compound of Formula IV (wherein R' is -COPh), which on desmethylation at 3 '-N-dimethyl group gives a compound of Formula V, which on alkylation with a reagent of
■3 -1 -J
Formula R CHO, R2 CO or R X (wherein X is halogen) gives a compound of Formula VI (wherein R is the same as defined earlier), which on reaction with a reagent selected from the group comprising of triphosgene and ethylene dicarbonate gives a compound of Formula VII, which on reaction with a organic base selected fi-om the group comprising of tetramethyl guanidine and trimethylamine gives a compound of Formula Vin, which on oxidation gives a compound of Formula EX, which on reaction with N,N'-carbonyl dimidazol 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 on fluorination gives a compound of Formula Xn, which is finally deprotected to give a compound of Formula XEH.
84. The process according to claim 83 wherein the hydrolysis of clarithromycin of Formula n to give a compound of Formula HI is carried out in the presence of an inorganic or organic acid selected fi-om the group consisting of hydrochloric acid, sulphuric acid and dichloroacetic acid.
85. The process according to claim 84 wherein the hydrolysis is carried out in hydrochloric acid.
86. The process according to claim 83 wherein the protection of a compound of Formula HI with a reagent of Formula R'20 or R'X to give a compound of Formula IV is carried out in a solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride and ethyl acetate.
87. The process according to claim 86 wherein the protection is carried out in dichloromethane.
88. The process according to claim 83 wherein the protection of a compound of Formula HI with a reagent of Formula R'20 or R'X is carried out in the presence of an organic base selected from the group consisting of triethylamine, pyridine, tributylamine and 4-N-(dimethylamino)pyridine.
89. The process according to claim 88 wherein the protection is carried out in triethylamine.
90. The process according to claim 83 wherein the desmethylation of a compound of Formula IV 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.
91. The process according to claim 90 wherein the desmethylation is carried out with N-iodosuccinimide.
92. The process according to claim 83 wherein the desmethylation of a compound of Formula W is carried out in a solvent selected from the group consisting acetonitrile, dichloromethane, dichloroethane, tetrahydrofiiran, ethyl acetate and mixture thereof
93. The process according to claim 92 wherein the desmethylation is carried out in acetonitrile and dichloromethane mixture.
94. The process according to claim 83 wherein the quenching of desmethylation is carried out in the presence of a quenching agent selected from the group consisting of potassium carbonate, sodium carbonate, sodium acetate and sodium bisulphite.
95. The process according to claim 83 wherein the alkylation of a compound of Formula V with a reagent of Formula RCHO, Ra^CO or RX to give a compound of Formula VI is carried out in a solvent selected from the group consisting of dimethylformamide, acetonitrile, methanol, acetone tetrahydrofiiran and mixture thereof
96. The process according to claim 95 wherein the alkylation is carried out in acetonitrile.
97. The process according to claim 95 wherein the alkylation is carried out in methanol.
98. The process according to claim 95 wherein the alkylation is carried out in methanol and acetone mixture.
99. The process according to claim 83 wherein the alkylation of a compound of Formula V
T T -J
with a reagent of Formula R CHO, R2 CO or R X is carried out in 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 diisopropyl ethylamine.
100. The process according to claim 99 wherein the alkylation is carried out in sodium hydrogen carbonate.
101. The process according to claim 99 wherein the alkylation is carried out in diisopropyl ethylamine.
102. The process according to claim 83 wherein the reaction of compound of Formula VI to give a compound of Formula Vn is carried out a solvent selected from the group consisting of chloroform, dichloromethane, carbon tetrachloride and dichloroethane.
103. The process according to claim 102 wherein the reaction is carried out in dichloromethane.
104. The process according to claim 83 wherein the reaction of compound of Formula VI to give a compound of Formula VII is carried out in an organic base selected from the group consisting of triethylamine, pyridine, tributylamine and 4- (dimethylamino)pyridine.
105. The process according to claim 104 wherein the reaction is carried out in the presence of pyridine.
106. The process according to claim 83 wherein the reaction of compound of Formula Vn to give a compound of Formula VIQ is carried out in a solvent selected from the group consisting of dimethylformamide, tetrahydroftiran and dimethylsulphoxide.
107. The process according to claim 106 wherein the reaction is carried out in dimethyformamide.
108. The process according to claim 83 wherein the oxidation of a compound of Formula VIII to give a compound of Formula DC is carried out with an oxidizing agent selected from the group consisting of Dess-Martin periodinane, N-chloro succinimide and l-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride.
109. The process according to claim 108 wherein the oxidation is carried out with Dess-Martin periodinane.
110. The process according to claim 83 wherein the oxidation of a compound of Formula VIII is carried out in a solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride and dimethylsulfoxide.
111. The process according to claim 110 wherein the oxidation is carried out in dichloromethane.
112. The process according to claim 83 wherein the reaction of compound of Formula IX with N, N'-carbonyl dimidazol to give a compound of Formula X is carried out in a solvent selected from the group consisting of dimethylformamide, tetrahydroftiran, acetonitrile and mixture thereof
113. The process according to claim 112 wherein the reaction is carried out in a mixture of
dimethylformamide and tetrahydrfuran.
114. The process according to claim 83 wherein the reaction of a compound of Formula DC with N, N'-carbonyl dimidazol is carried out in the presence of an inorganic base selected from the group consisting of sodium hydrogen carbonate, potassium carbonate, sodium acetate, sodium thiosulfate and sodium hydride.
115. The process according to claim 114 wherein the reaction is carried out in the presence of sodium hydride.
116. The process according to claim 83 wherein the reaction of a compound of Formula X with a reagent of Formula R-W-NH2 to give a compound of Formula XI is carried out in a solvent system selected from the group consisting of acetonitrile/water and dimethylformamide/water.
117. The process according to claim 116 wherein the reaction is carried out in water and acetonitrile mixture.
118. The process according to claim 83 wherein the fluorination of a compound of Formula XI to give a compound of Formula Xn is carried out in the presence of a fluorinating agent selected from the group consisting of N-fluorobenzene sulphonimide and selectfluor.
119. The process according to claim 83 wherein the fluorination is carried out in a solvent selected from the group consisting of dimethylformamide, tefrahydrofiiran and dimethylsulphoxide.
120. The process according to claim 119 wherein the reaction is carried out in dimethyformamide.
121. The process according to claim 119 wherein the reaction is carried out in tefrahydrofiiran.
122. The process according to claim 83 wherein the fluorination is carried out in the presence of an inorganic base selected from the group consisting of potassium carbonate, sodium acetate, sodium thiosulfate, potassium tert-butoxide and sodium hydride.
123. The process according to claim 122 wherein the fluorination is carried out in the presence of sodium hydride.
124. The process according to claim 122 wherein the fluorination is carried out in the presence of potassium tert-butoxide.
125. The process according to claim 83 wherein the deprotection of a compound of Formula XII to give a compound of Formula XIII is carried out in an alcohol selected from the group consisting of methanol, ethanol, propanol and isopropanol.
126. The process according to claim 125 wherein the deprotection is carried out in methanol.
127. A process for preparing a compound of Formula Xni, as shown in Scheme n of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs or polymorphs,
wherein R, W, R are the same as defined earlier, which comprises:
reacting a compound of Formula IV with a reagent selected from the group
comprising of triphosgene and ethylene dicarbonate to give a compound of
Formula XIV, which on reaction with an organic base selected from the group
comprising of tetramethyl guanidine and trimethyl amine gives a compound of
Formula XV, which on oxidation gives a compound of Formula XVI, which on
desmethylation at 3'-N-dimethyl group gives a compound of Formula XVn, which
on alkylation with a reagent of Formula RCHO, R2 CO or RX gives a compound of
Formula DC, which on fluorination gives a compound of Formula XVni, which on
reaction with N,N'-carbonyl diimidazol gives a compound of Formula XIX, which
on reaction with a compound of Formula R-W-NH2 gives a compound of Formula Xn, which is finally deprotected to give a compound of Formula XHI.
128. The process according to claim 127 wherein the reaction of a compound of Formula IV to give a compound of Formula XIV is carried out in a solvent selected from the group consisting of dichloromethane, carbon tefrachloride and dichloroethane.
129. The process according to claim 128 wherein the reaction is carried out in dichloromethane.
130. The process according to claim 127 wherein the reaction of a compound of Formula IV to give a compound of Formula XIV is carried out in the presence of an organic base selected from the group consisting of triethylamine, pyridine, tributylamine and 4-(dimethylamino)pyridine.
131. The process according to claim 130 wherein the reaction is carried out in the presence of pyridine.
132. The process according to claim 127 wherein the reaction of a compound of Formula XIV to give a compound of Formula XV is carried out in a solvent selected from the group consisting of dimethylformamide, tetrahydrofiiran and dimethylsulphoxide.
133. The process according to claim 132 wherein the reaction is carried out in dimethylformamide.
134. The process according to claim 127 wherein the oxidation of a compound of Formula XV to give a compound of Formula XVI is carried out with an oxidizing agent selected from the group consisting of Dess-Martin periodinane, N- chlorosuccinimide and l-ethyl-3(3-dimethyl aminopropyl) carbodiimide hydrochloride.
135. The process according to claim 133 wherein the oxidation is carried out with Dess-Martin periodinane.
136. The process according to claim 127 wherein the oxidation of a compound of Formula XV to give a compound of Formula XVI is carried out in a solvent selected from the group consisting of chloroform, dichloromethane, carbon tetrachloride, dimethylsulphoxide and dichloroethane.
137. The process according to claim 136 wherein the reaction is carried out in dichloromethane.
138. The process according to claim 127 wherein the desmethylation of a compound of Formula XVI to give a compound of Formula XVn is carried out in a solvent selected from the group consisting of acetonitrile, tefrahydrofiiran, dichloromethane, dichloroethane, ethyl acetate or mixture thereof.
139. The process according to claim 138 wherein the reaction is carried out in dichloromethane and acetonitrile mixture.
140. The process according to claim 127 wherein the desmethylation of a compound of Formula XVI to give a compound of Formula XVII is carried out in the presence of a desmethylating agent selected from the group consisting of N-iodosuccinimide and diisopropyl azodicarboxylate.
141. The process according to claim 140 wherein the desmethylation is carried out in the presence of N-iodosuccinimide.
142. The process according to claim 127 wherein the quenching of desmethylation reaction is carried out in the presence of a quenching agent selected from the group consisting of sodium bisulphite, sodium carbonate, potassium carbonate, sodium acetate and mixture thereof
143. The process according to claim 142 wherein the quenching is carried out in the presence of sodium bisulphite.
144. The process according to claim 127 wherein the alkylation of a compound of Formula XVH with a reagent of Formula R3CHO, Rz^CO or R X to give a compound of Formula DC is carried out in a solvent selected from the group consisting of dimethylformamide, acetonitrile, acetone, methanol, tetrahydrofixran and mixture thereof
145. The process according to claim 144 wherein the alkylation is carried out in acetonitrile.
146. The process according to claim 127 wherein the alkylation of a compound of Formula XVII is carried out in an inorganic or organic base selected from the group consisting of sodium hydrogen carbonate, potassium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate or diisopropylethylamine.
147. The process according to claim 146 wherein the alkylation is carried out in the presence of sodium hydrogen carbonate.
148. The process according to claim 127 wherein the fluorination of a compound of Formula XVII to give a compound of Formula XVm is carried out with a fluorinating agent selected from the group consisting of N-fluorobenzene sulfonimide and selectfluor.
149. The process according to claim 148 wherein the fluorination is carried out with N-fluorobenzenesulfonimide.
150. The process according to claim 127 wherein the fluorination of a compound of Formula XVH is carried out in a solvent selected from the group consisting of dimethylformamide, tetrahydrofiiran and dimethylsulphoxide.
151. The process according to claim 150 wherein the fluorination is carried out in dimethylform amide.
152. The process according to claim 150 wherein the fluorination is carried out in the presence of tetrahydrofuran.
153. The process according to claim 127 wherein the fluorination of a compound of Formula XVII is carried out in the presence of an inorganic base selected from the group consisting of potassium carbonate, sodium acetate, sodium thiosulphate, sodium hydride and potassium tert-butoxide.
154. The process according to claim 153 wherein the fluorination is carried out in the presence of sodium hydride.
155. The process according to claim 153 wherein the fluorination is carried out in the presence of potassium tert. butoxide.
156. The process according to claim 127 wherein the reaction of a compound of Formula XVIII with N,N'-carbonyl diimidazol to give a compound of Formula XDC is carried out in a solvent selected from the group consisting of dimethylformamide, tetrahydrofriran, acetonitrile and mixture thereof
157. The process according to claim 156 wherein the reaction is carried out in a mixture of dimethylformamide and tetrahydrofriran.
158. The process according to claim 127 wherein the reaction of a compound of
Formula XVHI with N,N'-carbonyldiimidazol is carried out in the presence of an
inorganic base selected from the group consisting of sodium hydrogen carbonate,
potassium carbonate, sodium acetate, sodium thiosulphate and sodium hydride.
159. The process according to claim 158 wherein the reaction is carried out in the presence of sodium hydride.
160. The process according to claim 127 wherein the reaction of a compound of Formula XIX with a compound of Formula R-W-NH2 to give a compound of Formula Xn is carried out in a solvent system selected from the group consisting of acetonitrile/water and dimethylformamide/water.
161. The process according to claim 160 wherein the reaction is carried out in acetonirile/water.
162. The process according to claim 127 wherein the deprotection of a compound of Formula XII to give a compound of Formula Xni is carried out in an alcohol selected from the group consisting of methanol, ethanol, propanol and sopropanol.
163. The process according to claim 162 wherein the reaction is carried out in methanol.
164. A process for preparing a compound of Formula XIH, , as shown in Scheme m of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs or polymorphs,
wherein R, W and R are the same as defined earlier, which comprises:
fluorination of a compound of Formula XVI to give a compound of Formula XX, which on reaction with N,N'-carbanoyl diimidazole gives a compound of Formula XXI, which onreaction with a compound of Formula R-W-NH2 gives a compound of Formula XXII, which on deprotection gives a compound of Formula XXIII, which on desmethylation at 3'-N-dimethyl group gives a compound of Formula XXIV, which on alkylation with a reagent of Formula RCHO, RaCO or RX gives a compound of Formula XHI.
165. The process according to claim 164 wherein the fluorination of a compound of Formula XVI to give a compound of Formula XX is carried out with a fluorinating agent selected from the group consisting of N-fluorobenzene sulfonimide and selectfluor.
166. The process according to claim 165 wherein the fluorination is carried out with N-fluorobenzene sulfonimide.
167. The process according to claim 164 wherein the fluorination of a compound of Formula XVI to give a compound of Formula XX is carried out in a solvent selected from the group consisting of dimethylformamide, tetrahydrofuran and dimethylsulphoxide.
168. The process according to claim 167 wherein the fluorination is carried out in dimethylformamide.
169. The process according to claim 167 wherein the fluorination is carried out in tetrahydrofuran.
170. The process according to claim 164 wherein the fluorination of a compound of Formula XVI is carried out in the presence of an inorganic base selected from the group
consisting of potassium carbonate, sodium hydride, sodium acetate, sodium thiosulphate or potassium tert-butoxide.
171. The process according to claim 170 wherein the fluorination is carried out in the presence of sodium hydride.
172. The process according to claim 170 wherein the fluorination is carried out in the presence of potassium tert. butoxide.
173. The process according to claim 164 wherein the reaction of a compound of Formula XX with N,N'-carbonyl diimidazol to give a compound of Formula XXI is carried out in a solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, acetonitrile and mixture thereof.
174. The process according to claim 173 wherein the reaction is carried out in a mixture of dimethylformamide and tetrahydrofuran.
175. The process according to claim 164 wherein the reaction of a compound of Formula XX with N,N'-carbonyl diimidazol is carried out in an inorganic base selected from the group consisting of sodium hydrogen carbonate, potassium carbonate, sodium acetate, sodium thiosulphate and sodium hydride.
176. The process according to claim 175 wherein the reaction is carried out in the presence of sodium hydride.
177. The process according to claim 164 wherein the reaction of a compound of Formula XXI with a compound of Formula R-W-NH2 to give a compound of Formula XXII is carried out in a solvent system selected from the group consisting of acetonitrile/water or dimethylformamide/water.
178. The process according to claim 177 wherein the reaction is carried out in acetonitrile/water.
179. The process according to claim 164 wherein the deprotection of a compound of Formula XXII to give a compound of Formula XXIII is carried out in an alcohol selected from the group consisting of methanol, ethanol, propanol and isopropanol.
180. The process according to claim 179 wherein the deprotection is carried out in methanol.
181. The process according to claim 164 wherein the desmethylation of a compound of Formula XXin to give a compound of Formula XXIV is carried out in a solvent
selected from the group consisting of acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate and mixture thereof
182. The process according to claim 181 wherein the desmethylation is carried out in acetonitrile.
183. The process according to claim 164 wherein the desmethylation of a compound of Formula XXIII to give a compound of Formula XXIV is carried out in the presence of a desmethylating agent selected from the group consisting of N-iodo succinimide and diisopropylazodicarboxylate.
184. The process according to claim 183 wherein the desmethylation is carried out in the presence of N-iodosuccinimide.
185. The process according to claim 164 wherein the quenching of desmethylation is carried out in the presence ofa quenching agent selected from the group consisting of sodium bisulphite, sodium carbonate, potassium carbonate, sodium acetate or mixture thereof
186. The process according to claim 185 wherein the quenching is carried out in the presence of sodium bisulphite.
187. The process according to claim 164 wherein the alkylation of a compound of Formula XXIV with a reagent of Formula R3CHO, R32CO or R3X to give a compound of Formula XIII is carried out in a solvent selected from the group consisting of dimethylformamide, acetonitrile, methanol, acetone, tefrahydrofiiran and mixture thereof
188. The process according to claim 187 wherein the alkylation is carried out in acetonitrile.
189. The process according to claim 164 wherein the alkylation of a compound of Formula XXIV is carried out in the presence of an inorganic or organic base selected from the group consisting of sodium hydrogen carbonate, potassium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate and diisopropyl ethylamine.
190. The process according to claim 189 wherein the alkylation is carried out in the presence of sodium hydrogen carbonate.
191. A process for preparing of a compound of Formula Xin, as shown in Scheme IV of the
accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, stereoisomers, prodrugs or polymorphs,
wherein R, W and R3 are the same as defined earlier,
which comprises:
deprotection of a compound of Formula XX (wherein R1 is COPh) to give a
compound of Formula XXV, which on desmethylation at 3-N'-dimethyl group gives a
compound of Formula XXVI, which on alkylation with a reagent of Formula
R3CHO, R32CHO or R3X gives a compound of Formula XXVH,
which on protection with a reagent of Formula R'20 or R'X (wherein X is halogen) gives
a compound ofFormulaXVin (wherein R'=C0CH3), which on reaction with N,N'-
carbonyl diimidazol gives a compound of Formula XrX, which on reaction with a
compound of Formula R-W-NH2 gives a compound of Formula Xn, which on
deprotection gives a compound of Formula XIII.
192. The process according to claim 191 wherein the deprotection of a compound of Formula XX to give a compound of Formula XXV is carried out in an alcohol selected from the group consisting of methanol, ethanol, propanol and isopropanol.
193. The process according to claim 192 wherein the deprotection is carried out in methanol.
194. The process according to claim 191 wherein the desmethylation of a compound of Formula XXV to give a compound of Formula XXVI is carried out in the presence of a desmethylating agent selected from the group consisting of N-iodosuccinimide and diisopropylazodicarboxylate.
195. The process according to claim 194 wherein the desmethylation is carried out in the presence of N-iodosuccinimide.
196. The process according to claim 191 wherein the desmethylation of a compound of Formula XXV is carried out in a solvent selected fi^om the group consisting of acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate and mixture thereof
197. The process according to claim 196 wherein the desmethylation is carried out in acetonitrile.
198. The process according to claim 191 wherein the quenching of desmethylation is carried out in the presence of a quenching agent selected from the group consisting of sodium bisulphite, sodium carbonate, potassium carbonate, sodium acetate and mixture thereof
199. The process according to claim 198 wherein the quenching is carried out in the presence of sodium bisulphite.
200. The process according to claim 191 wherein the alkylation of a compound of Formula XXVI with a reagent of Formula RCHO, R2C0 or RX to give a compound of Formula XXVII is carried out in a solvent selected from the group consisting of dimethylformamide, acetonitrile methanol, acetone, tetrahydrofiiran and mixture thereof
201 The process according to claim 200 wherein the alkylation is carried out in acetonitrile.
202. The process according to claim 191 wherein the alkylation of a compound of Formula XXVI is carried out in an inorganic or organic base selected from the group consisting of sodium hydrogen carbonate, potassium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate and diisopropyl ethylamine.
203. The process according to claim 202 wherein the alkylation is carried out in the presence of sodium hydrogen carbonate.
204. The process according to claim 191 wherein the protection of a compound of Formula XXVII with a reagent of Formula R2'0 or R'X to give a compound of Formula XVni is carried out in a solvent selected from the group consisting of dichloromethane, dichloroethane, carbon tetrachloride, chloroform and acetone.
205. The process according to claim 204 wherein the protection is carried out in acetone.
206. The process according to claim 191 wherein the protection of a compound of Formula XXVII with a reagent of Formula R2O or RX is carried out in the presence of an inorganic base selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate.
207. The process according to claim 206 wherein the hydroxyl protection is carried out in the presence of potassium carbonate.
208. The process according to claim 191 wherein the reaction of a compound of Formula XVIII with N,N'-carbonyl diimidazol to give a compound of Formula XIX is carried out in a solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, acetonitrile and mixture thereof
209. The process according to claim 208 wherein the reaction is carried out in a mixture of dimethylformamide and tetrahydrofuran.
210. The process according to claim 191 wherein the reaction of a compound of Formula XVni with N, N'-carbonyldiimidazol is carried out in the presence of an inorganic base selected from the group consisting of sodium hydrogen carbonate, potassium carbonate, sodium acetate, sodium thiosulphate and sodium hydride.
211. The process according to claim 210 wherein the reaction is carried out in the presence of sodium hydride.
212. The process according to claim 191 wherein the reaction of a compound of Formula XIX with a compound of Formula R-W-NH2 to give a compound of Formula Xn is carried out in a solvent system selected from the group consisting of acetonitrile/water and dimethylformamide/water.
213. The process according to claim 212 wherein the reaction is carried out in acetonitrile/water.
214. The process according to claim 191 wherein the reaction of a compound of Formula Xn to give a compound of Formula XIII is carried out in an alcohol selected from the group consisting of methanol, ethanol, propanol and isopropanol.
215. The process according to claim 214 wherein the reaction is carried out in methanol.
216. The processes for the preparation of compounds of Formula XIQ, substantially as herein described and illusfrated by example herein.