Field of the Invention
The present invention provides acylide derivatives, which can be used as antibacterial agents. Compounds disclosed herein can be used for the treatment or prevention of a condition caused by or contributed to by gram positive, gram negative or anaerobic bacteria, more particularly against bacterium such as Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp.. Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae. Processes for the preparation of disclosed compounds are provided, as well as pharmaceutical compositions containing the disclosed compounds, and method of treating bacterial infections.
Background of the Invention
The first generation macrolides erythromycin A and the early derivatives are characterized by bacteriostatic or bactericidal activity for most gram-positive bacteria, atypical pathogens, and many community acquired respiratory infections and in patients with penicillin allergy. However, erythromycin A causes numerous drug-drug interactions, has relatively poor absorption, poor local tolerance, loses its antibacterial activity under acidic conditions by degradation and the degraded products are known to be responsible for undesired side effects. (Itoh, Z et al, Am. J. Physiol, 247: 688, 1984; Omura, S et al, J. Med Chem, 30: 1943, 1987). Various erythromycin A derivatives have been prepared to overcome the acid instability and other problems associated with it.
Roxithromycin, clarithromycin and azithromycin have been developed to address the limitation of erythromycin A. Both clarithromycin and azithromycin have proved to be important drugs in the treatment and prophylaxis of atypical Mycobacterial infections in patients with HIV.
Macrolides have proved to be effective drugs in the treatment of many respiratory tract
infections. However, increasing resistance among S. pneumoniae has prompted the search for
new compounds that retain the favorable safety profile, and a spectrum of activity and are
confined to respiratory pathogens. Consequently, numerous investigators have prepared
chemical derivatives of erythromycin A in an attempt to obtain analogs having modified or
improved profiles of antibiotic activity.
WO 99/11651 discloses 3-descladinosyl-6-0-substituted erythromycin derivatives, which have
been said to be useful as antibacterial agents.
WO 02/12260 discloses macrolide antibiotics.
WO 01/10878, 01/10879 and 01/10880 disclose novel erythromycin derivatives stated to have
potent antibacterial effects on erythromycin-resistant bacteria and Haemophilus influenzae.
U.S. Patent No. 6,140,479 discloses erythromycin derivatives stated to be having antibacterial
activity.
Summarv of the Invention
The present invention provides acylide derivatives, which can be used in the treatment or prevention of bacterial infection, and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs of these compounds having same type of activity are also provided.
Pharmaceutical compositions containing the disclosed compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of bacterial infection.
Other object will be set forth in accompanying description which follows and in part will be apparent from the description or may be learnt by the practice of the invention. In accordance with one aspect, there are provided compounds having the structure of Formula I, as shown in the accompanied drawings, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs, wherein
R1 can be
—hydrogen
—hydroxyl protecting group R2 and R3 can be
— hydrogen
— alkyl (with the provisio that R and R simultaneously can not be methyl)
—alkenyl
—alkynyl —cycloalkyl
—aryl —heterocycle
—aralkyi
—(heterocycle)alkyl
R4 can be
—hydrogen —alkyl —alkenyl —alkynyl
R+ can be
—aryl
—heterocycle —alkyl R can be
—no atom —aryl
—heterocycle R' can be
—alkyl
- -(CH2)q-U-V
wherein q can represent an integer I to 4, U can represent
o alkenyl
o alkynyi and V can represent
o hydrogen
o aryl
o heterocycle W can be
— hydrogen
— -(CH2)m- wherein m can represent an integer 2 to 6 and
o alkylene group can be optionally interrupted by groups independently chosen from oxygen, sulfur and -NR6-, where R6 can be chosen from hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl, (heterocyclyl)alkyl, alkynyi, aryl or aralkyl
o one of the hydrogen atom of alkylene chain can be optionally replaced by
• alkyl
• hydroxy
• alkoxy Y can be
— -Q(CH2)k-, wherein k can represent an integer 1 to 6, Q can represent
o no atom
o -NR^- wherein R^ can represent hydrogen or alkyl o oxygen one of the hydrogen atom of alkylene chain can be optionally replaced by o alkyl
o hydroxy
o alkoxy Z can be
—oxygen —sulphur —NOR8 wherein R8 can represent
o hydrogen
o alkyl
o aralkyl In one particular embodiment, there are provided compounds wherein W can be -(CH2)m- and R
can be heterocycle substituted with -NHCONHR9 ,wherein R9
can be alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, aralkyl, (heterocycle)alkyl or heterocyclyl.
In another particular embodiment, there are provided compounds wherein W can be hydrogen or
-(CH2)m, wherein alkylene group can be optionally interrupted by groups independently chosen
from oxygen, sulfur and -NR6-, wherein R6 is chosen from hydrogen, alkyl, cycloalkyl, alkenyl,
heterocyclyl, (heterocyclyl)alkyl, alkynyl, aryl or aralkyl, more particularly by oxygen and R
can be no atom, aryl or heterocyclyl.
In another particular embodiment, there are provided compounds wherein W can be hydrogen or
-(CH2)m- , wherein one of the hydrogen atom of alkylene chain can be optionally replaced by
alkyl, hydroxy or alkoxy, more particularly by alkyl.
In accordance with a second aspect, there is provided a method for treating or preventing a
mammal suffering from a condition caused by or contributed to by gram positive, gram negative
or anaerobic bacteria, comprising administering to said mammal, a therapeutically effective
amount of a compound or a pharmaceutical composition disclosed herein.
The bacterial infection may be caused by bacterium such as Staphylococci, Streptococci,
Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp.,
Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae.
The said conditions may be, for example, community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or bone and joint infections, and other bacterial infections such as mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease.
In accordance with a third aspect, there 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, cycloalkoxy, -NHC0R10, -NHC00R10 -0C0R10 or -C0R10, wherein R10 is alkyl, aryl or heterocycle. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl and butyl, and the like.
As used herein the term "alkenyl or alkynyl" stands for unsaturated hydrocarbon having two to six carbon atoms. One or more hydrogen atom (s) of said alkenyl or alkynyl can be replaced by halogen, hydroxy, mercapto, alkoxy or thioalkyl. Examples of alkenyl and alkynyl include, but are not limited to, ethylene, propylene, ethynyl and propynyl, and the like. As used herein the term "cycloalkyl" refers to saturated carbocyclic ring having three to seven carbon atoms. One or more hydrogen atom (s) of said cycloalkyl can be replaced by halogen, hydroxy, mercapto, alkoxy or thioalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl and cyclopentyl, and the like. As used herein the term "halogen or halo" refers to fluorine, chlorine, bromine or iodine.
As used herein the term "hydroxyl-protecting group" includes, but are not limited to, acyl, aroyi,
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 refers to alkyl or cycloalkyl.
As used herein the term "haloalkyl" refers to alkyl of which one or more hydrogen (s) is/are
replaced by halogen.
As used herein the term "aryl" stands for an aromatic radical having 6 to 14 carbon atoms.
Examples of aryl include, but are not limited to, phenyl, napthyl, anthryl and biphenyl, and the
like.
As used herein the term "aralkyl" stands for an aryl radical having 7 to 14 carbon atoms, which
is bonded to an alkylene chain. Examples of aralkyl include, but are not limited to, benzyl,
napthylmethyl, phenethyl and phenylpropyl, and the like.
As used herein the term "heterocycle" refers to non-aromatic or aromatic ring system having one
or more heteroatom(s) such as nitrogen, sulphur or oxygen, the ring system includes mono, bi or
tricyclic which is optionally attached via heteroatom. Examples of heterocycles include, but not
limited to, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl,
benzothiazolyl, benzothienyl, benzotriazolyl, dihydroimidazolyl, dihydropyranyl,
dihydrofuranyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl,
imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl,
isoxazolyl, morpholinyl, napthyridinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, purinyl,
pyrazinyl, pyrazolinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl.
pyrrolopyridinyl, imidazolpyridinyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl,
thiazolidinyl, thiazolyl, thienyl, and the like.
As used herein the term "(heterocycle) alkyl" stands for heterocycle, which is bonded to an alkylene chain. Examples of heterocycle alkyl include, but are not limited to, isothiazolidinyl ethyl, isothiazolyl propyl, pyrazinyl methyl, pyrazolinyl propyl and pyridyl butyl, and the like. The said aryl and heterocycle may optionally be substituted with one or more substituent(s) independently selected from the group consisting of hydroxy, halogen, nitro, mercapto, cyano, alkyl, haloalkyl, alkoxy, thioalkyl, optionally substituted aryl, optionally substituted heterocyclyl, -NHCONHR9, wherein R9 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, (heterocycle)alkyl or heterocyclyl, -NR11R12 -CONR11R12 -COOR11, -CONHR11, -OCOR11, -COR11, -NHSO2R", and -SO2NHR", wherein R11 and R12 are independently selected from the group comprising of hydrogen and alkyl.
Detailed Description of the Invention
The compounds disclosed herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in schemes I, II and III of the accompanied drawings.
The compound of Formula XII can be prepared according to Scheme I, as shown in the accompanied drawings. Thus, clarithromycin of Formula II is hydrolyzed to give a compound of Formula III, which on protection with a reagent of Formula R120 or R'X (wherein X is halogen) gives a compound of Formula IV (wherein R1 is -COPh), which on reaction with a reagent gives a compound of Formula V, which on reaction with an organic base gives a compound of Formula VI, which on desmethylation at 3'-N-dimethyl group gives a compound of Formula VII,
which on alkylation with a reagent of Formula R CHO, R 2CO or R X gives a compound of
Formula VIII (wherein R3 is the same as defined earlier), which on acylation with a reagent of
Formula R5YCOOH, (R5YC0)20, R5YCOX or RVC00R10 (wherein R10 is leaving group such
as pivaloyl, p-toleuensulfonyl, isobutoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl) gives
a compound of Formula IX (wherein Y and R5 are the same as defined earlier), which on
reaction with N, N'-carbonyl diimidazole gives a compound of Formula X, which on reaction
with a compound of Formula R-W-NH2 gives a compound of Formula XI (wherein R and W are
the same as defined earlier), which is finally deprotected to give a compound of Formula XII.
The hydrolysis of clarithromycin of Formula II to give a compound of Formula III 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 III to give a compound of Formula IV can be
carried out in a solvent, for example, dichloromethane, dichloroethane, carbon tetrachloride,
chloroform or ethyl acetate.
The hydroxyl protection of a compound of Formula III to give a compound of Formula IV can be
carried out in the presence of an organic base, for example, triethylamine, pyridine,
tributylamine, 4-N-dimethylaminopyridine or diisopropyl ethyl amine.
The reaction of a compound of Formula IV to give a compound of Formula V can be carried out
in the presence of a reagent, for example, triphosgene or ethylene carbonate.
The reaction of a compound of Formula IV to give a compound of Formula V can be carried out
in a solvent, for example, chloroform, dichloromethane, carbon tetrachloride or dichloroethane.

The reaction of a compound of Formula IV can be carried out in the presence of an organic base,
for example, triethylamine, pyridine, tributylamine , 4-N-dimethylaminopyridine or diisopropyl
ethyl amine.
The reaction of a compound of Formula V to give a compound of Formula VI can be carried out
in a solvent, for example, dimethylformamide, tetrahydrofuran or dimethylsulphoxide.
The reaction of a compound of Formula V to give a compound of Formula VI can be carried out
in the presence of an organic base, for example, tetramethyl guanidine, pyridine, trimethylamine
or diisopropyl ethyl amine.
The desmethylation of a compound of Formula VI to give a compound of Formula VII can be
carried out in the presence of a demethylating agent, for example, N-iodosuccinamide, iodine in
acetic acid or diisopropyl azodicarboxylate.
The desmethylation of a compound of Formula VI can be carried out in a solvent, for example,
acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride,
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, potassium carbonate, sodium acetate, sodium carbonate or
mixture thereof
The alkylation of a compound of Formula VII with a reagent of Formula R3X to give a
compound of Formula VIII can be carried out in a solvent, for example, dimethylformamide,
acetonitrile or tetrahydrofuran.
The alkylation of a compound of Formula VII to give a compound of Formula VIII can be
carried out in an inorganic or organic base, for example, sodium hydrogen carbonate, potassium
carbonate, sodium acetate, sodium thiosulfate, sodium hydride, pyridine, triethylamine and
diisopropyl ethyl amine.
The alkylation of a compound of Formula VII can also be carried out with a reagent of Formula
R3CHO or R.3 2O 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 VIII to give a compound IX can be carried out in a
solvent, for example, dichloromethane, dichloroethane, acetone, chloroform, carbon
tetrachloride, ethyl acetate or tetrahydrofuran.
The reaction of a compound of Formula VIII to give a compound IX can be carried out in the
presence of an inorganic or organic base, for example, sodium bicarbonate, potassium carbonate,
triethylamine, pyridine, tributylamine, 4-N-dimethylaminopyridine or diisopropyl ethyl amine.
The reaction of a compound of Formula VIII to give a compound IX can be carried out in the
presence of an activating agent, for example, N, N'-dicyclo hexyl carbodiimide or l-ethyl-3- (3-
dimethylaminopropyl) carbodiimide hydrochloride.
The reaction of a compound of Formula IX with N, N'-carbonyl diimidazole to give a compound
of Formula X can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran
or mixture thereof
The reaction of a compound of Formula IX can be carried out in the presence of an inorganic
base, for example, sodium hydrogen carbonate, potassium carbonate, diisopropyl ethyl amine 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, for example, acetonitrile, water,
dimethylformamide or mixture thereof
The deprotection of a compound of Formula XI to give a compound of Formula XII can be
carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol.
The compound of Formula XV can be prepared by following Scheme II, as shown in the
accompanied drawings. Thus, the compound of Formula X is reacted with ammonia to give a
compound of Formula XIII (wherein R3, R1, Y and R5 are the same as defined earlier), which on
cyclization gives a compound of Formula XIV, which is, finally, deprotected to give a compound
of Formula XV.
The reaction of a compound of Formula X with ammonia to give a compound of Formula XIII
can be carried out in a solvent, for example, acetonitrile, water, dimethylformamide or mixture
thereof.
The cyclization of a compound of XIII to give a compound of Formula XIV can be carried out in
a solvent, for example, dichloromethane, dichloroethane, acetone, dimethyformamide, ethyl
acetate or tetrahydrofuran.
The cyclization of a compound of XIII to give a compound of Formula XIV can be carried out in
the absence or in the presence of an organic base, for example, n- butyl lithium lithium-3-
aminopropanamide or alkali-alkoxides selected as potassium tert-butoxide.
The deprotection of a compound of Formula XIV to give a compound of Formula XV can be
carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol.
The compound of Formula XIX can be prepared by following Scheme III, as shown in the
accompanied drawings. Thus, compound of Formula XVI (prepared by following Scheme I) with
a compound of Formula XVII to give a compound of Formula XVIII (wherein R1, R9, R3 Y and R5 are the same as defined earlier), which is finally deprotected to give a compound of Formula XIX.
The reaction of a compound of Formula XVI with a compound of Formula XVII to give a compound of Formula XVIII can be carried out in a solvent, for example, dichloromethane, dichloroethane, acetone, ethyl acetate, chloroform, carbon tetrachloride or tetrahydrofuran. The deprotection of a compound of Formula XVIII to give a compound of Formula XIX can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol. In the above scheme, where the specific bases, activating agents, solvents, etc., are mentioned, it is to be understood that bases, activating agents, solvents, etc., known to those skilled in the art may be used. Similarly, the reaction temperature and duration may be adjusted according to the desired needs.
The compounds disclosed herein possess antibacterial activity against gram-positive, gram-negative and anaerobic bacteria. They are useful as antibacterial agents for the treatment of bacterial infections in human and animal. Compounds of the present invention useful for such purpose are listed below (also shown in Table I):
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-
methyl-12,1 l-[oxycarbonyl-((4-(benzoimidazol-l-yl)-pentyl)-imino)] erythromycinA
(Compound No. 1),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-
methyl-12,1 l-[oxycarbonyl-((4-(benzoimidazol-l-yl)-pentyl)-imino)] erythromycinA
(Compound No.2),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-(IH-imidazo[4,5-b]pyridin-l-yl)-pentyl)-imino)] erythromycin A (Compound No.3),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H -imidazo[4,5-b]pyridin-3-yl)-pentyl)-imino)] erythromycin A (Compound No.4),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,] l-[oxycarbonyl-(3-(4-pyridin-3-yl-phenoxy)-imino)]erythromycin A (Compound No.5),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbony l-(( 1 -(9-(4-amino-butyl)-9H-purin-6-yl)-3-butyl)-urea)-imino)]erythromycin A (Compound No.6),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-((l-(9-(4-amino-butyl)-9H-purin-6-yl)-3-(2,6-difluoro-phenyl)-urea)-imino)]erythromycin A (Compound No.7),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-(( 1 -allyl-3-(9-(4-amino-butyl)-9H-purin-6-yl)-urea)-imino)]erythromycin A (Compound No.8),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-(( 1 -(9-(4-amino-butyl)-9H-purln-6-yl)-3-(4-fluoro-phenyl)-urea)-imino)]erythromycin A (Compound No.9),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-((3-(3-pyridin-3-yl-phenoxy)-propyl)-imino)] erythromycin A (Compound No. 10),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-imino)]erythromycin A (Compound No.l 1),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyi)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-imino)]erythromycin A (Compound No. 12),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-
methyl-12,1 l-[oxycarbonyl-((3-(3-thiophen-3-yl-phenoxy)-propyl)-imino)]erythromycinA
(Compound No. 13),
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites and polymorphs.

Table-I (Formula I, wherein R- R^= CH3; R''= C2H5; Z=0; Y

-CH2-; R'=H)

(Formula Removed)

As used herein the term "polymorphs" includes all crystalline forms and amorphous forms for compounds described herein. In addition, some of the compounds described herein may form solvates with water (i.e. hydrate, hemihydrate or sesquihydrate) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
The phrase "pharmaceutically acceptable salts" denotes salts of the free base, which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. Suitable pharmaceutically acceptable salts may be prepared from an inorganic or organic acid. Example of such inorganic acids include, but not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous (nitrile salt), nitric (nitrate salt), carbonic, sulfuric, phosphoric acid and like. Appropriate organic acids include, but not limited to, aliphatic, cycloaliphoric, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumeric, pyruvic, aspartic, glutamic, benzoic, anthranilic.
mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-
hydroxyethanesulfonic, sulfanilic, stearic, algenic, beta-hydroxybutyric,
cyclohexylaminosulfonic, galactaric and galacturonic acid and the like.
The term "pharmaceutically acceptable solvates" refers to solvates with water (i-e hydrates) or pharmaceutically acceptable solvents, for example solvates with ethanol and the like. Such solvates are also encompassed within the scope of the disclosure. Furthermore, some of the crystalline forms for compounds described herein may exist as polymorphs and as such are intended to be included in the scope of the disclosure.
The present invention also includes within its scope prodrugs of these agents. In general, such prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "design of prodrugs", ed. H Bundgaard and, Elsevier, 1985.
The disclosed compounds may get metabolized in vivo and these metabolites are also encompassed within the scope of this invention.
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 eanantiomer 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.
There may be tautomers for some of the disclosed compounds, and the present invention covers all the possible isomers including tautomers and mixtures thereof
In another aspect, there is provided pharmaceutical composition, which may be administered to an animal for treatment orally, topically, rectally, internasally, or by parenteral route. The pharmaceutical compositions of disclosed compounds comprise a pharmaceutically effective amount of a compound described herein formulated together with one or more pharmaceutically acceptable carriers. "The term pharmaceutically acceptable carriers" is intended to include nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
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 In the case of capsules, tablets, pills, the dosage form may also comprise
bufferring agents.
The solid preparation of tablets, capsules, pills and granules can be prepared with coating and
shells, for example, enteric coating and other coatings well known in the pharmaceutical
formulating art.
Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions,
solutions, suspensions, syrups and elixirs. For liquid form preparation, the active compound is
mixed with water or other solvent, solubilizing agents and emulsifiers, for example, ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, for example, cottonseed,
groundnut, corn, germ, olive, castorand sesame oil), glycerol, and fatty acid esters of sorbitan
and mixture thereof Besides inert diluents, the oral composition can also include adjuants, for
example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring
agents and perfuming agents.
Injectable preparations, for example, sterile injections, aqueous suspensions may be formulated
according to the art using suitable dispersing or wetting and suspending agent. Among the
acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic
sodium chloride.
Dosage form for tropical or transdermal administration of a compound of the present invention
includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
The active compound is admixed under sterile condition with a pharmaceutically acceptable
carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations,
eardrops, eye ointments, powder and solution are also contemplated as being within the scope of
this invention.
The pharmaceutical preparation is in unit dosage form. In such form, the preparation is
subdivided into unit doses containing appropriate quantities of the active component. The unit
dosage form can be packaged preparation, the package containing discrete capsules, powders, in
vials or ampoules, and ointments capsule, sachet, tablet, gel, cream itself or it can be the
appropriate number of any of these packaged forms.
The quantity of active compound in unit dose of preparation may be varied or adjusted from less
than 1 mg to several grams according to the particular application and potency of the active
ingredient.
In therapeutic use as agents for treating bacterial infections the compounds utilizing in the
pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to
about 40 mg per kilogram daily. The dosages, however, may be varied depending upon the
requirements of the patients and the compound being employed.
Determination of the proper dosage for a particular situation is within the smaller dosages, which
are less than the optimum dose. Small increments until the optimum effect under the daily
dosage may be divided and administered in portion during the day if desired.
Examples set forth below 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
Scheme I
Preparation of R-W-NH?
(i) When W= -(CH2)4 -
Example 1: Preparation of 9-(4-aminobutyl)-9H-purin-6-amine
It was prepared by following the procedure given in US Patent No. 5,635,485.
(ii) When W^(CH2)3-CH(CH3)-
Example 2: Preparation of 4-(3H)-imidazo[4,5-b1pvridin-3-vl) pentan-1-amine and 4-(lH-imidazor4,5-6] pyridin-l-yl) pentan-1-amine
Step 1: Preparation of 5-(tert-butyl-dimethyl-silanvloxv) pentan-2-ol
1,4 pentanediol (5 g, 48.0 mmoles, 1.0 eq) was taken in dimethylformamide (10 ml) and cooled
to 0°C. To it imidazole (4.9 g, 72 mmole, 1.5 eq) was added and reaction mixture was stirred for
about 10 minutes followed by the addition of tert-butyl-dimethyl-silanyloxy chloride (8.0 g, 52.8
mmoles, 1.1 eq) in dimethylformamide (5 ml). The reaction mixture was the allowed to stir at
room temperature for about 20 hour, poured into ice-cold water and extracted with ethyl acetate.
Evaporation of ethyl acetate layer gave the product.
Yield: 10.6 g
Step 2: Preparation of methanesulphonic acid-4-(tert-butvl-dimethvl-silanyloxv)-l-methyl-butyl ester
5-(tert-butyl-dimethyl-silanyloxy) pentan-2-ol (10.5 g, 47.9 mmoles, 1.0 eq.) was taken in
dichloromethane (20ml) and cooled to 0°C. To this triethyl amine (10 ml, 71.9 mmole, 1.5 eq.)
was added and the reaction mixture was stirred for about 10 min followed by the addition of
methane sulphonyl chloride (4.5 ml, 57.5 mmoles, 1.2 eq). The reaction mixture was stirred for
about 1 hour at 0°C, quenched by addition of aqueous sodium bicarbonate solution and extracted
with dichloromethane. Evaporation of dichloromethane layer gave the product.
Yield: 12.8 g
Step 3: Preparation of 3-(4-{[tert -butyl(dimethvl)silvnoxv}-l-methylbutyl)-3H-imidazo[4.5-b]pvridine ( isomer [al ) and l-(4-([tert-butvl(dimethyl")silvl1oxv}-l-methvlbutvl)-lH-imidazo[4,5-6]pvridine (isomer [b])
3H-imidazo[4,5-6] pyridine (3.5 g, 29.4 mmol, 1.0 eq) was taken in dimethylformamide (10 ml) and cooled to 0°C. To this sodium hydride (1.8 g, 44.1 mmol, 1.5 eq) was added in portions and after the additions were over, the contents were stirred for about 15 min. Then methanesulphonic acid-4- (tert-butyl-dimethyl-silanyloxy)-l-methyl-butyl ester (11.4 g, 38.2 mmol, 1.3 eq) in dimethylformamide (5 ml) was added at 0°C and the reaction mixture was allowed to come to room temperature and stirred for about 24 hour, poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with water and dried with brine and sodium sulphate and concentrated under reduced pressure to get the crude product. It was then purified by column chromatography using 100-200 mesh silica gel and hexane: acetone: triethyl amine to get the two isomers.
Yield: isomer [a]: 2.5 g isomer [b]: 1.5 g Step 4: Preparation of 4-(3H-imidazo[4,5-6] pyridin-3-vl) pentan-1-ol
To the 3-[4-(tert-butyl-dimethyl-silanyloxy)-l-methyl-butyl]-3H-imidazo[4,5-b] pyridine (2.4 g, 0.0075 moles, 1 eq.) was added tetra-n-butylamonium fluoride (3.5 ml, 0.0135 mol, 1.8 eq.) and the reaction mixture was heated at 55°C for about 45 minutes. The reaction mixture was poured in water and extracted with ethyl acetate, washed with water, brine and dried over anhydrous sodium sulphate. The organic layer was concentrated and vacuum dried. Yield: 1.4 g The following compound was prepared by following the same step
- 4-(lH-imidazo[4,5-6] pyridin-1-yl) pentan-1-ol
Step 5: Preparation of methane sulphonic acid 4-(3H)imidazo[4,5-b1pvridin-3-vl-pentvl ester To 4-(3H-imidazo[4,5-6] pyridin-3-yl) pentan-1-ol (3 g, 0.0146 moles, 1 eq.) was added dichloromethane (10ml) and it was cooled to 0°C. Tri ethyl amine (3 ml, 0.0219 moles, 1.5 eq) was added to it followed by methane sulphonyl chloride (1.35 ml, 0.01752 moles, 1.2 eq.). The reaction mixture was stirred for about 45 minutes, quenched with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous sodium sulphate. The organic layer was concentrated and vacuum dried.
Yield: 3.2 g The following compound was prepared by following the same step
- Methane sulphonic acid 4-(lH-imidazo[4,5-Z)] pyridin-1-yl) pentyl ester
Step 6: Preparation of 2-[4-(3H-imidazo [4,5-b] pyridin-3-yl-pentvl)-isoindole-l, 3-dione
To phthalimide (1.1 g, 0.0074 mole, 1 eq.) in dry dimethylformamide (5 ml) was added sodium
hydride (0.448 g, 0.01122 moles, 1.5 eq.) in portions. After about 20 minutes, methane sulphonic
acid 4-(3H)- imidazo[4,5-b]pyridin-3-yl-pentyl ester (3.2 g, 0.01122 moles, 1.5 eq.) dissolved in
dry dimethylformamide (5 ml) was added. It was allowed to stir for about 14 hours. The reaction
mixture was poured in ice-cold water and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried over anhydrous sodium sulphate.
Yield=2 g
The following compound was prepared by following the same step
-2-[4-(lH-imidazo[4,5-Z>] pyridin-1-yl) pentyl]-isoindole-l, 3-dione
Step 7: Preparation of 4-(3H-imidazo[4.5-b] pyridin-3-yl) pentan-1- amine
2-[4-(3H-imidazo [4,5-b] pyridin-3-yl-pentyl)-isoindole-l, 3-dione (2 g, 5.98 mmoles, 1 eq) was
taken in ethanol (20ml) and hydrazine monohydrate (6 ml, 11.9 mmol, 2 eq) was added to it. The
reaction mixture was heated at 70°C for about 4 hours. It was cooled to room temperature and
solid obtained was filtered through celite bed. The filtrate was concentrated to get the crude
product, which was purified over 100-200 mesh silica gel column using dichloromethane and
methanol as eluant.
Yield: 0.22 g, 36%
The following compound was prepared by following the same step
-4-(lH-imidazo[4,5-Z)] pyridin-1-yl) pentan-1-amine
The following compound was prepared by following example 2
- 4-(lH-benzimidazol-l-yl) pentan-1-amine
(iii) When W= -(CH2)3-0-
Example 3: Preparation of 3-(4-pyridin-3-vl phenoxy) propan-1-amine
Step 1: Preparation of pvridin-3-boronic acid
3-bromo pyridine (5g) was dissolved in dry tetrahydrofuran (20 ml), cooled to -78°C and to it tri-
isopropyl borate (14.68ml) was added, followed by addition of butyl lithium (15% in hexane,
21ml). The reaction mixture was stirred at -78°C for about 4 hours, pH was adjusted to about 7,
it was extracted with ethyl acetate and concentrated to get white solid.
Yield: 1.2g
Step 2: Preparation of 2-[3-(3-bromo-phenoxy)-propvl]-isoindole-l,3-dione
To 3-bromo phenol (5.5 g, 0.03178 moles, 1 eq), dry dimethylformamide (30 ml) was added. It
was cooled to 0°C. Then sodium hydride (1.9 g, 0.0476 moles, 1.5 eq) was added in portions.
After 30 minutes, N-3-bromopropyl phthalimide (10.2 g, 0.0381 moles, 1.2 eq) was added. The
reaction mixture was stirred for about 3 hours. It was quenched by pouring reaction mixture into
ice cold water. The precipitate was filtered and vaccum dried.
Yield: 9 g
Step 3: Preparation of 2-(3-[3-(pyridin-3-vl)-phenoxv]-propyl|-isoindole-l,3-dione
Pyridin-3-boronic acid (0.75 g, 6.1]mmoles, 1.1 eq.), 2-[3-(3-bromo-phenoxy)-propyl]-
isoindole-1, 3-dione (2 g, 5.5 mmoles, 1 eq.) and potassium carbonate (3 g, 22.2 mmoles, 4 eq.)
were taken in a round bottom flask and degassed for about 1 hour. Dry dimethylformamide (15
ml) was added. The reaction mixture was than flushed with argon for about 15 minutes. Tetrakis
(triphenylphosphine) palladium (0) (0.32 g, 0.27 moles, 0.05 eq.) was added to it. The reaction
mixture was heated at 80°C for about 12 hours. It was quenched with water and extracted with
ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium
sulphate.
Yield = 0.2 g
Step 4: Preparation of 3-(4-pyridin-3-yl phenoxy) propan-1-amine
2-{3-[3-(pyridin-3-yl)-phenoxy]-propyl}-isoindole-l,3-dione (0.2g) was taken in ethanol (10 ml)
and hydrazine monohydrate (0.2ml) was added to it . The reaction mixture was heated at 60°C
for about 4 hours. It was cooled to room temperature and solid obtained was filtered through
celite bed. The filtrate was concentrated to get the crude product, which was purified using
dichloromethane and methanol as eluant.
Yield: 0.13g
The following compounds were prepared following the above procedure
-3-[3-(3-thienyl) phenoxy] propan-1-amine
—3-(3-pyridin-3-yl-phenoxy) propan-1-amine
Preparation of compound of Formula 111
To a solution of hydrochloric acid (IN, 250 ml) was added clarithromycin of Formula 11 (25g,
33.4 mmol) at ambient temperature. The reaction mixture was neutralized with solid sodium
bicarbonate and the aqueous layer was extracted with ethyl acetate. Organic layer was washed
with water, brine, and dried over anhydrous sodium sulphate. The solvent was removed under
reduced pressure to give the desired product. The crude product was crystallized using ethyl
acetate- hexane mixture.
Preparation of compound of Formula IV
To a solution of compound of Formula III (1 equiv) in dry dichloromethane was added benzoic
anhydride (2.5 equiv), triethylamine (6 equiv) and stirred at ambient temperature for about 30
hours. Reaction was quenched by aqueous sodium bicarbonate solution. The aqueous layer was
extracted with dichloromethane, washed successively with water, brine, and dried over
anhydrous sodium sulphate and then the solvent was removed under reduced pressure to give a
crude product. The crude product was crystallized by using ethyl acetate - hexane mixture.
Preparation of compound of Formula V
To a solution of compound of Formula IV (1 equiv) in dichloromethane at 0°C was added
triphosgene (1.5 equiv) with stirring. Then to it was added pyridine (15 equiv) slowly. After
complete addition, reaction mixture was stirred for about 3h at 0-5°C. Reaction was quenched by
drop wise addition of water, was diluted with dichloromethane and washed with water, brine,
dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the
desired product.
Preparation of compound of Formula VI
To a solution of a compound of formula V (1 equiv) in dimethylformamide was added
tetramethyl guanidine (2.2 equiv) and reaction mixture was heated at 90°C for about 8 hours.
Reaction mixture was cooled to an ambient temperature and water was added and extracted with
ethyl acetate. Organic layer was washed with water followed by brine, dried over anhydrous
sodium sulphate and concentrated under reduced pressure to obtain the desired product.
Preparation of compound of Formula VII
To a solution of compound of Formula VI (1 equiv) in dry acetonitrile: dichloromethane (2:1)
cooled to 0°C, was added N-iodosuccinimide (2 equiv). The reaction mixture was stirred with
sodium bisulphite solution followed by stirring with sodium carbonate solution.
Dichloromethane was evaporated under reduced pressure. The aqueous residue 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 obtain the crude product,
which was purified by silica gel column chromatography (thoroughly neutralized with triethyl
amine) using 10-20% acetone in hexane to give the product.
Preparation of compound of Formula VIII
To a solution of compound of Formula VII (1 equiv) in acetonitrile was added solid sodium
bicarbonate (5 equiv) and a reagent of Formula R3X (6 equiv) under argon at ambient
temperature for about 24 hours. The reaction mixture was diluted with ethyl acetate and washed
with water followed by brine, dried over anhydrous sodium sulphate and concentrated under
reduced pressure to get the crude product, which on purification by silica gel column
chromatography (thoroughly neutralized with triethylamine) using 10-20% acetone in hexane
yielded the product.
Preparation of compound of Formula IX
To a solution of compound of Formula VIII (1 equiv) in dichloromethane was added a reagent of
Formula R^YCOOH (2.5 equiv), 4-N-dimethylaminopyridine (2.5 equiv) and N, N'-
dicyclohexylcarbodiimide (2.5 equiv) followed by the addition of pyridine (4 equiv). The reaction mixture was stirred for about 18-24 hours and then filtered through celite bed. Filtrate was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the crude product, which was purified by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-20% acetone in hexane. Preparation of compound of Formula X
To a solution of compound of Formula IX (1 equiv) in dimethylformamide: tetrahydrofuran (3:2) cooled to 0°C , was added N, N'-carbonyldiimidazole (3 equiv), followed by sodium hydride (3 equiv) in one lot. Reaction was quenched by addition of ice-cold water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, brine dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product. Preparation of compound of Formula XI
A compound of Formula X (1 equiv) and a compound of Formula R-W-NH2 (3 equiv) were taken in 10%) water in acetonitrile and heated at 70-75°C. Reaction mixture was cooled to an ambient temperature; acetonitrile was evaporated under reduced pressure. The resulting residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using 25-30%) acetone in hexane to afford the desired product. Preparation of compound of Formula XII
A solution of compound of Formula XI (0.6 mmol) in methanol was refluxed. Reaction mixture was cooled to an ambient temperature and methanol was evaporated under reduced pressure. Purification of the crude residue was done over silica gel (thoroughly neutralized by triethyl amine) using 30-35%) acetone in hexane or 2-8%) methanol in dichloromethane.
Scheme II
Preparation of compound of Formula XIII
A compound of Formula X (0.437 mmoles) was dissolved in dimethylformamide (10 ml).
Ammonia gas was passed through it for about 20 minutes at 0°C. The reaction mixture was
stirred for about 2 hours. It was extracted with ethyl acetate. The organic layer was washed with
water, brine and dried over sodium sulphate.
Preparation of compound of Formula XIV
Method A
The reaction mixture of above step was allowed to stir for about 24 hours at room temperature.
The solvent was evaporated and the compound was purified over silica gel using 7% methanol in
dichloromethane.
Method B
A compound of Formula XIII (0.462 mmoles) was dissolved in tetrahydrofuran (10 ml).
Potassium tert-butoxide (0.509 mmoles) was added to it portionwise at 0°C. The reaction mixture
was stirred overnight. It was extracted with ethyl acetate, washed with brine, water and dried
over sodium sulphate.
Preparation of compound of Formula XV
A solution of compound of Formula XIV (0.46 mole) in methanol (8 ml) was refluxed. Reaction
mixture was cooled to an ambient temperature and methanol was evaporated under reduced
pressure. Purification of the residue was done over silica gel (thoroughly neutralized by triethyl
amine) using 30-35% acetone in hexane or 2-8% methanol in dichloromethane.
Scheme III
Preparation of compound of Formula XVIII
Compound of Formula XVI (0.4 mmol) and compound of Formula XVII (1.1 mmol) were taken
in dichloromethane and stirred at 25°C for about 14 hours. Dichloromethane (10 ml) was
evaporated under reduced pressure and the resulting residue was purified by column
chromatography using hexane: acetone: triethyl amine as the eluant.
Preparation of compound of Formula XIX
Compound of Formula XVIII (0.2 mmol) was taken in methanol (5 ml) and refluxed for about
18 hours. The reaction mixture was cooled to 30°C, the solvent was evaporated under reduced
pressure and the resulting residue was purified by column chromatography over 100-200-mesh
silica get using dichloromethane-methanol as eluant.
The following compounds were prepared by following the above general procedures.
-ll,12-dideoxy-3-0-decladinosyl-3-0- (2-pyridyl acetyl)- 5-0- (3'-N-desmethyl-3'-N-ethyl)-6-O- methyl - 12,ll-[oxycarbonyl- ((4-(benzoimidazol-l-yl)- pentyl)-imino)] erythromycin A (Compound No. 1) Mass: 934.41
-ll,12-dideoxy-3-0-decladinosyl-3-0- (2-pyridyl acetyl)-5-0- (3'-N-desmethyl-3'-N-allyl)- 6-0- methyl - 12,11- [oxycarbonyl- ((4-(benzoimidazol-l-yl)-pentyl)-imino)] erythromycin A (Compound No.2) Mass: 946.36
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-(lH-imidazo[4,5-b]pyridin-l-yl)-pentyl)-imino)] erythromycin A (Compound No.3) Mass: 947.49
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-((4-(3H-imidazo[4,5-b]pyridin-3-yl)-pentyl)-imino)] erythromycin A (Compound No.4) Mass: 947.35
-ll,12-dideoxy-3-0-decladinosyl-3-0- (2-pyridyl acetyl)-5-0- (3'-N-desmethyl-3'-N-allyl)-6-O-methyl-12, Il-[oxy carbonyl- (3-(4-pyridin-3-yl-phenoxy)-imino)] erythromycin A (Compound No.5) Mass: 972.48
-ll,12-dideoxy-3-0-decladinosyl-3-0- (2-pyridyl acetyl)-5-0- (3'-N-desmethyl-3'-N-alIyl)-6-O-methyl-12, 11-[oxycarbonyl- ((l-(9-(4-amino-butyl)-9H-purin-6-yl)-3-butyl)-urea)-imino)] erythromycin A (Compound No.6)

Mass: 1048.67
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,11 -[oxycarbonyl-((l -(9-(4-amino-butyl)-9H-purin-6-yl)-3-(2,6-difluoro-phenyl)-urea)-imino)]erythromycin A (Compound No.7) Mass: 1104.63
-ll,12-dideoxy-3-0-decladinosyl-3-0- (2-pyridyl acetyl)-5-0- (3'-N-desmethyl-3'-N-allyl)-6-O-methyl-12, 1 l-[oxycarbonyl- ((l-allyl-3- (9-(4-amino-butyl)-9H-purin-6-yl)-urea)-imino)] erythromycin A (Compound No.8) Mass: 1032.40
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,1 l-[oxycarbonyl-((l-(9-(4-amino-butyl)-9H-purin-6-yl)-3-(4-fluoro-phenyl)-urea)-imino)]erythromycin A (Compound No.9) Mass: 1086.32
-ll,12-dideoxy-3-0-decladinosyl-3-0- (2-pyridyl acetyl)-5-0- (3'-N-desmethyl-3'-N-allyl)-6-O-methyl-12, 1 l-[oxycarbonyl- ((3-(3-pyridin-3-yl-phenoxy)-propyl)-imino)] erythromycin A (Compound No. 10) Mass: 971.26
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-
methyl-12,1 l-[oxycarbonyl-imino)]erythromycin A (Compound No.l 1)
Mass: 760.49
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-
methyl-12,1 l-[oxycarbonyl-imino)]erythromycin A (Compound No. 12)
Mass: 760.56
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridyl acetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-
methyl-12,1 l-[oxycarbonyl-((3-(3-thiophen-3-yl-phenoxy)-propyl)-imino)]erythromycin A
(Compound No. 13)
Mass: 976.67
Pharmacological activity
Compounds disclosed herein displayed antibacterial activity in vitro especially against strains
which are resistant to macroiides 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,
catheter 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
Streaked the cultures on TSA for aerobic cultures and MHA with 5% sheep blood for fastidious
cultures. Incubated aerobic cultures and fastidious cultures in a CO2 incubator (5% CO2) for 18-
24 hours at 37°C. Took 3-4 well isolated colonies and made saline suspension in sterile densimat
tubes. Adjusted the turbidity of the culture to 0.5-0.7 Mc Farland standard (1.5 x 10^ Colony
Forming Unit (CFU)/ml). Diluted the cultures 10 fold in saline to get inoculum size of
approximately l-2x 10 organisms/ml.
Preparation of drug concentration
Prepared 1 mg/ml concentration of stock solution of drug in dimethylsulfoxide/distilled
water/solvent given in National Committee for Clinical Laboratory Standards (NCCLS) manual.
Prepared serial two fold dilutions of the compounds and standard drugs as per NCCLS manual.
Stock solution can be changed according to the need of the experiment.
Preparation of Agar Plates
Added 2 ml of respective drug concentration to 18 ml of Molten Mueller Hinton agar to get the
required range; for example 0.015 |4.g/ml - 16 |4,g/ml. For fastidious culture added 1 ml of sheep
blood in Molten Mueller Hinton agar.
Prepared one control MHA and MHA with 5% sheep blood plates without antibiotic for each set.
Prepared one MHA and MHA with 5% sheep blood plates without antibiotic for determining
quality check for media.
Preparation of Teflon template
Replicated 1 |ug of each culture on each plate with the help of replicator (Denley's multipoint
replicator). Allowed the spots to dry and incubated the plates for 18-24 hours at 37°C. For
fastidious culture incubated at 37 °C in CO2 incubator. Noted the results 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 MIC.
Read and plotted the quality control (QC) strains on the QC chart for agar dilution method, if the
MlCs were within the range, interpreted the results by comparing MICs of standards against all
organisms with those of test compounds.
Precautions & Quality Control Measures
Quality Control Strains
S. aureus ATCC 29213
E. faecalis ATCC 292\2
E. coli ATCC 25922
Ps. aeruginosa ATCC 27853 Visually checked all 60 cultures for purity.
Media Control: Performed NCCLS disc diffusion assay using 10 µg discs of Gentamicin (Difco) against Ps. aeruginosa ATCC 27853. A zone diameter of 16-21 mm should be considered for
optimum cation (Magnesium and Calcium) content of the media. Plotted the diameter 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 I00-SI2,
Vol. 22 No. 1 (January 2002)
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended within the scope of the present invention.
(Table Removed)

WE CLAIM:
1. A compound having the structure of Formula I, as shown in the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs, wherein R1'is
—hydrogen
—hydroxyl protecting group R2 and R3 are
— hydrogen
— alkyl (with the provisio that R and R simultaneously are not methyl) —alkenyl
—alkynyl
—cycloalkyl —aryl
—heterocycle —aralkyl —(heterocycle)alkyl
— hydrogen —alkyl —alkenyl —alkynyl
—aryl
—heterocycle
—alkyl
—no atom
—aryl
—heterocycle
R'is
—alkyl
- -(CH2)q-U-V
wherein q represents an integer 1 to 4, U represents
o alkenyl
o alkynyl and V represents
o hydrogen
o aryl
o heterocycle W is
— hydrogen
(CH2)m- wherein m represents an integer 2 to 6 and
o alkylene group is optionally interrupted by groups independently chosen from
oxygen, sulfur and -NR6-, where R6 is chosen from hydrogen, alkyl, cycloalkyl, alkenyl,
heterocyclyl, (heterocyclyl)alkyl, alkynyl, aryl and aralkyl
o one of the hydrogen atom of alkylene chain is optionally replaced by
• alkyl
• hydroxy
• alkoxy Y is
— -Q(CH2)k-, wherein k represents an integer 1 to 6, Q represents
o no atom
o -NR7- wherein R7 represents hydrogen or alkyl
o oxygen one of the hydrogen atom of alkylene chain is optionally replaced by
o alkyl
o hydroxy
o alkoxy Z is
—oxygen —sulphur —NOR8 wherein R8 represents
o hydrogen
o alkyl
o aralkyl
2. A compound according to claim 1 wherein R is no atom.
3. A compound according to claim 1 wherein R is optionally substituted heterocycle, wherein the optional substituent is -NHCONHR9, wherein R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, (heterocycle) alkyl and heterocyclyl.
4. A compound according to claim 3 wherein R9 is alkyl or alkenyl.
5. A compound according to claim 4 wherein R9 is butyl or propenyl.
6. A compound according to claim 3 wherein R9 is optionally substituted aryl wherein the optional substituent is halogen.
7. A compound according to claim 6-wherein the optional substituent is fluorine.
8. A compound according to claim 1 wherein R is optionally substituted aryl wherein the optional substituent is heterocycle.
9. A compound according to claim 8 wherein the optional substituent is pyridyl or thienyl.
10. A compound according to claim 1 wherein R is selected from benziimidazol-1-yl, (lH-imidazo[4,5-b] pyridin-1-yl, (3H-imidazo[4,5-b] pyridin-3-yl, (4-pyridin-3-yl)-phenyl, 1- butyl -3- (9H-purin-6-yl) urea, l-(2,6-difluoro-phenyl)-3- (9H-purin-6-yl) urea, l-allyl-3- (9H-purin-6-yl)-urea, l-(4-fluoro-phenyl)-3- (9H-purin-6-yl urea, (3-pyridin-3-yl)-phenyl and (3-thiophen-3-yl)-phenyl.
11. A compound according to claim 1 wherein W is hydrogen.
12. A compound according to claim 1 wherein W is alkylene group optionally interrupted by groups independently selected from oxygen, sulfur and -NR6-, where R6 is selected from hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl, (heterocyclyl)alkyl, alkynyl, aryl and aralkyl .
13. A compound according to claim 12 wherein alkylene group is interrupted by oxygen.
14. A compound according to claim 1 wherein W is alkylene group wherein one of the hydrogen atoms of alkylene chain is optionally replaced by alkyl, hydroxy and alkoxy.
15. A compound according to claim 14 wherein one of the hydrogen atoms of alkylene chain is replaced by alkyl.
16. A compound according to claim 15 wherein one of the hydrogen atoms of alkylene chain is replaced by methyl.
17. A compound according to claim 1 wherein R2 and R3 are respectively methyl and alkyl.
18. A compound according to claim 17 wherein R2 and R3 are respectively methyl and ethyl.
19. A compound according to claim 1 wherein R2 and R3are respectively methyl and alkenyl.

20. A compound according to claim 19 wherein R2 and R3 are respectively methyl and propenyl.
21. A compound according to claim 1 wherein R5 is monocyclic heterocycle having
nitrogen as heteroatom (s).
22. A compound according to claim 21 wherein R5 is 2-pyridine.
23. A compound according to claim 21 wherein R5 is 3-pyridine.
24. A compound according to claim 1 wherein R1 is hydrogen, Z is oxygen and R4 and R' are alkyl.
25. A compound according to claim 24 wherein R' is methyl and R4 is ethyl.
26. A compound which is:
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-ethyl)-6-0-methyl-12,11 -[oxycarbonyl-((4-(benzoimidazol-1 -yl)-pentyl)-imino)] erythromycin A (Compound No. 1),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-al lyl)-6-0-methyl-12,11 -[oxycarbonyI-((4-(benzoimidazol-1 -yl)-pentyl)-imino)] erythromycin A (Compound No.2),
-lj,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(lH-imidazo[4,5-b]pyridin-l-yl)-pentyl)-imino)] erythromycin A (Compound No.3),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-((4-(3H-imidazo[4,5-b]pyridin-3-yl)-pentyl)-imino)] erythromycin A (Compound No.4),
-11,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3 '-N-desmethyl-3 '-N-allyl)-6-0-methyl-12,ll-[oxycarbonyl-(3-(4-pyridin-3-yl-phenoxy)-imino)]erythromycin A (Compound No.5),
-1 l,12-dideoxy-3-0-decladinosyl-3-0- (2-pyridylacetyl)-5-0- (3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12, 1 l-[oxycarbonyl- ((l-(9-(4-amino-butyl)-9H-purin-6-yl)-3-butyl)-urea)-imino)] erythromycin A (Compound No.6),
-1 l,12-dideoxy-3-0-decladinosyl-3-0- (2-pyridylacetyl)-5-0- (3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12, 11-[oxycarbonyl- ((l-(9-(4-amino-butyl)-9H-purin-6-yl)-3-(2,6-difluoro-phenyl)-urea)-imino)] erythromycin A (Compound No.7),
-1 l,12-dideoxy-3-0-decladinosyl-3-0- (2-pyridylacetyl)-5-0- (3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12, 11-[oxycarbonyl- ((l-allyl-3- (9-(4-amino-butyl)-9H-purin-6-yl)-urea)-imino)] erythromycin A (Compound No.8),
-1 l,12-dideoxy-3-0-decladinosyl-3-0- (3-pyridylacetyl)-5-0- (3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12, ll-[oxycarbonyl- ((l-(9-(4-amino-butyl)-9H-purin-6-yl)-3-(4-fluoro-phenyl)-urea)-imino)] erythromycin A (Compound No.9),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,l ]-[oxycarbonyl-((3-(3-pyridin-3-yl-phenoxy)-propyl)-imino)] erythromycin A (Compound No. 10),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,l l-[oxycarbonyl-imino)]erythromycin A (Compound No.l 1),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(3-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,l l-[oxycarbonyl-imino)]erythromycin A (Compound No.12),
-ll,12-dideoxy-3-0-decladinosyl-3-0-(2-pyridylacetyl)-5-0-(3'-N-desmethyl-3'-N-allyl)-6-0-methyl-12,l]-[oxycarbonyl-((3-(3-thiophen-3-yl-phenoxy)-propyl)-imino)]erythromycin A (Compound No. 13),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
stereoisomers, tautomers, racemates, prodrugs, metabolites and polymorphs thereof
27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the preceeding claims together with pharmaceutically acceptable carrier, excipients or diluents.
28. 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 1-26.
29. 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 27.
30. The method according to claim 28 or 29 wherein the said condition is selected from the group consisting of community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or
bone and joint infections, and other bacterial infections, for example, mastitis, catether infection, foreign body or prosthesis infections.
31. The method according to claim 28 or 29 wherein the said bacterium is gram positive, gram negative or anaerobic bacteria.
32. The method according to claim 31 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.
33. The method according to claim 32 wherein the bacterium is cocci.
34. The method according to claim 33 wherein the cocci is drug resistant.
35. A process for preparing a compound of Formula XII, as shown in the Scheme I of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites or polymorphs, wherein
R3 is
— hydrogen
— alkyl (with the provisio that R3 is not methyl)
—alkenyl
—alkynyl
—cycloalkyi
—aryl
—heterocycle
—aralkyl
—(heterocycle)alkyl
R5 is
-aryl
—heterocycle —alkyl R is
—no atom —aryl
—heterocycle W is
— hydrogen
— -(CH2)m-wherein m represents an integer 2 to 6 and
o alkylene group is optionally interrupted by groups independently chosen from oxygen, sulfur and -NR6-, where R6 is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl,. (heterocyclyl)alkyl, alkynyl, aryl and aralkyl
o one of the hydrogen atom of alkylene chain is optionally replaced by o alkyl o hydroxy o alkoxy Y is
— -Q(CH2)k-, wherein k represents an integer 1 to 6, Q represents
o no atom
7 7
o -NR - wherein R represents hydrogen or alkyl o oxygen one of the hydrogen atom of alkylene chain is optionally replaced by o alkyl o hydroxy o alkoxy which method comprises hydrolyzing clarithromycin of Formula II, to give a
compound of Formula III, which on protection with a reagent of Formula R120 or
R1X (wherein X is halogen) gives a compound of Formula IV (wherein R' is -COPh),
which on reaction with a reagent gives a compound of Formula V, which on reaction
with an organic base gives a compound of Formula VI, which on desmethylation at 3'-N-dimethyl group gives a compound of Formula VII, which on alkylation with a reagent of Formula R3CHO, R32CO or R3X gives a compound of Formula VIII (wherein R'' is the same as defined earlier), which on acylation with a reagent of Formula R^YCOOH, (R5YC0)20, R5YCOX or R5YC00R10 (wherein R10 is leaving group such as pivaloyl, p-toleuensulfonyl, isobutoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl) gives a compound of Formula IX (wherein Y and R5 are the same as defined earlier), which on reaction with N, N'-carbonyl diimidazole gives a compound of Formula X, which on reaction with a compound of Formula R-W-NH2 gives a compound of Formula XI (wherein R and W are the same as defined earlier), which is finally deprotected to give a compound of Formula XII of the accompanied drawings.
36. The process according to claim 35 wherein the hydrolysis of clarithromycin of Formula II to give a compound of Formula III is carried out in the presence of an inorganic or organic acid selected from the group consisting of hydrochloric acid, sulphuric acid and dichloroacetic acid.
37. The process according to claim 36 wherein the hydrolysis is carried out in hydrochloric acid.
38. The process according to claim 35 wherein the hydroxyl protection of a compound of Formula III 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.
39. The process according to claim 38 wherein the hydroxyl protection is carried out in dichloromethane.
40. The process according to claim 35 wherein the hydroxyl protection of a compound of Formula III to give a compound of Formula IV is carried out in the presence of an organic base selected from the group comprising of triethylamine, pyridine, tributylamine 4-N-dimethylaminopyridine and diisopropyl ethylamine.
41. The process according to claim 40 wherein the protection is carried out in triethylamine.
42. The process according to claim 35 wherein the reaction of compound of Formula IV to give a compound of Formula V is carried out in the presence of reagent selected from the group comprising of triphosgene and ethylene carbonate.
43. The process according to claim 42 wherein the reaction is carried out in the presence of triphosgene.
44. The process according to claim 35 wherein the reaction of compound of Formula IV is carried out a solvent selected from the group comprising of chloroform, dichloromethane, carbon tetrachloride and dichloroethane.
45. The process according to claim 44 wherein the reaction is carried out in dichloromethane.
46. The process according to claim 35 wherein the reaction of compound of Formula IV is carried out in an organic base selected from the group comprising of triethylamine, pyridine, tributylamine 4-N-dimethylaminopyridine and diisopropylethylamine.
47. The process according to claim 46 wherein the reaction is carried out in the presence of pyridine.
48. The process according to claim 35 wherein the reaction of compound of Formula V to give a compound of Formula VI is carried out in a solvent selected from the group comprising of dimethylformamide, tetrahydrofuran and dimethylsulphoxide.
49. The process according to claim 48 wherein the reaction is carried out in dimethyform amide.
50. The process according to claim 35 wherein the reaction of compound of Formula V is carried out in the presence of an organic base selected from the group comprising of tetramethyl guanidine, pyridine, trimethylamine and diisopropylethylamine.
51. The process according to claim 50 wherein the reaction is carried out in the presence of tetramethyl guanidine.
52. The process according to claim 35 wherein the desmethylation of compound of Formula VI to give a compound of Formula VII is carried out in the presence of a demethylating agent selected from the group comprising of N-iodosuccinamide, iodine in acetic acid and diisopropyl azodicarboxylate.
53. The process according to claim 52 wherein the desmethylation is carried out with N-iodosuccinamide.
54. The process according to claim 35 wherein the desmethylation of compound of Formula VI is carried out in a solvent selected from the group comprising acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform, carbon tetrachloride, dichloroethane and mixture thereof
55. The process according to claim 54 wherein the desmethylation is carried out in acetonitrile and dichloromethane mixture.
56. The process according to claim 35 wherein the quenching of desmethylation is carried out in the presence of a quenching agent selected from the group comprising of potassium carbonate, sodium carbonate, sodium acetate, sodium bisulphite and mixture thereof.
57. The process according to claim 35 wherein the alkylation of a compound of Formula VII with a compound of Formula R3X to give a compound of Formula VIII is carried out in a solvent selected from the group comprising of dimethylformamide, acetonitrile and tetrahydrofuran.
58. The process according to claim 57 wherein the alkylation is carried out in acetonitrile.
59. The process according to claim 35 wherein the alkylation of compound of Formula
VII to give a compound of Formula VIII is carried out in the presence of an inorganic
or organic base selected from the group comprising of sodium hydrogen carbonate,
potassium carbonate, sodium acetate, sodium thiosulfate, sodium hydride, pyridine,
triethylamine and diisopropyl ethyl amine.
60. The process according to claim 59 wherein the alkylation is carried out in sodium bicarbonate.
61. The process according to claim 59 wherein the alkylation is carried out in diisopropylamine.
62. The process according to claim 35 wherein the reaction of a compound of Formula
VIII with a compound of Formula R5YCOOH to give a compound IX is carried out in
a solvent selected from the group comprising of dichloromethane, dichloroethane,
acetone, ethyl acetate, chloroform, carbon tetrachloride and tetrahydrofuran.
63. The process according to claim 62 wherein the reaction is carried out in dichloromethane.
64. The process according to claim 35 wherein the reaction of a compound of Formula VIII to give a compound IX is carried out in the presence of an inorganic or organic base selected from the group comprising of sodium bicarbonate, potassium carbonate, triethylamine, pyridine, tributylamine, 4-N-dimethylaminopyridine and diisopropyl ethylamine.
65. The process according to claim 64 wherein the reaction is carried out in the presence of pyridine.
66. The process according to claim 35 wherein the reaction of a compound of Formula VIII to give a compound IX is carried out in the presence of an activating agent selected from the group comprising of N, N'-dicyclohexyl carbodiimide and I-ethyl-3-(3-dimethylaminopropyl) carbodiimode hydrochloride.
67. The process according to claim 66 wherein the reaction is carried out in the presence of N, N'-dicyclohexyl carbodiimide.
68. The process according to claim 35 wherein the reaction of a compound of Formula IX to give a compound of Formula X is carried out in a solvent selected from the group comprising of dimethylformamide, tetrahydrofuran and mixture thereof.
69. The process according to claim 68 wherein the reaction is carried out in dimethylformamide and tetrahydrofuran mixture.
70. The process according to claim 35 wherein the reaction of a compound of Formula IX to give a compound of Formula X is carried out in the presence of an inorganic base
selected from the group comprising of sodium hydrogen carbonate, potassium carbonate, sodium hydride and diisopropyl ethylamine.
71. The process according to claim 70 wherein the reaction is carried out in the presence sodium hydride.
72. The process according to claim 35 wherein the reaction of a compound of Formula X to give a compound of Formula XI is carried out in a solvent selected from the group comprising of acetonitrile, water, dimethylformamide and mixture thereof
73. The process according to claim 72 wherein the reaction is carried in water and acetonitrile mixture.
74. The process according to claim 35 wherein the deprotection of a compound of Formula XI to give a compound of Formula XII is carried out in the presence of an alcohol selected from the group comprising of methanol, ethanol, propanol and isopropanol.
75. The process according to claim 74 wherein the deprotection is carried out in the presence of methanol.
76. A process for preparing a compound of Formula XV, as shown in the Scheme II of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites or polymorphs, wherein
R 3is
— hydrogen
— alkyl (with the provisio that R is not methyl) —alkenyl
—alkynyl —cycloalkyl
—aryl
—heterocycle —aralkyl
—(heterocycle)alkyl RMS —aryl
—heterocycle —alkyl Y is
— -Q(CH2)k-, wherein k represents an integer 1 to 6, Q represents
o no atom
o -NR7- wherein R7 represents hydrogen or alkyl
o oxygen one of the hydrogen atom of alkylene chain is optionally replaced by
o alkyl
o hydroxy
o alkoxy which method comprises reacting the compound of Formula X, with ammonia to give
a compound of Formula XIII (wherein R , R , Y and R are the same as defined
earlier),which on cyclization gives a compound of Formula XIV, which is, finally,
deprotected to give a compound of Formula XV of the accompanied drawings.
77. The process according to claim 76 wherein the reaction of a compound of Formula X with ammonia to give a compound of Formula XIII is carried out in a solvent selected from the group consisting of acetonitrile, water, dimethylformamide and mixture thereof
78. The process according to claim 77 wherein the reaction is carried out in dimethylformamide.
79. The process according to claim 76 wherein the cyclization of a compound of XIII to give a compound of Formula XIV is carried out in a solvent selected from the group consisting of dichloromethane, dichloroethane, acetone, dimethyformamide, ethyl acetate and tetrahydrofuran.
80. The process according to claim 79 wherein the cyclization is carried out in tetrahydrofuran.
81. The process according to claim 79 wherein the cyclization is carried out in dimethylformamide.
82. The process according to claim 76 wherein the cyclization of a compound of XIII to give a compound of Formula XIV is carried out in the absence or in the presence of an organic base selected from the group consisting of n- butyl lithium, lithium-3-aminopropanamide and alkali-alkoxides selected as potassium tert-butoxide.
83. The process according to claim 82 wherein the cyclization is carried out in the presence of potassium tert-butoxide.
84. The process according to claim 76 wherein the deprotection of a compound of Formula XIV to give a compound of Formula XV is carried out in an alcohol selected from the group consisting of methanol, ethanol, propanol and isopropanol.
85. The process according to claim 84 wherein the deprotection is carried out in methanol.
86. A process for preparing a compound of Formula XIX, as shown in the Scheme III of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites or polymorphs, wherein
R3 is
— hydrogen
— alkyl (with the provisio that R is not methyl) —alkenyl
—alkynyl —cycloalkyl —aryl
—heterocycle —aralkyl —(heterocycle)alkyl
R5 is
—aryl
—heterocycle — alkyl Y is
— -Q(CH2)k-, wherein k represents an integer 1 to 6, Q represents
o no atom
o -NR7- wherein R7 represents hydrogen or alkyl o oxygen
one of the hydrogen atom of alkylene chain is optionally replaced by o alkyl o hydroxy o alkoxy
R9s
— alkyl
— alkenyl
— alkynyl
— cycloalkyl
— aryl
— aralkyl
— (heterocycle)alkyl
— heterocyclyl
which method comprises reacting a compound of Formula XVI (prepared by
following Scheme I) ,with a compound of Formula XVII, to give a compound of Formula XVIII (wherein R1,R9 R3 Y and R5 are the same as defined earlier), which is finally deprotected to give a compound of Formula XIX of the accompanied drawings.
87. The process according to claim 86 wherein the reaction of a compound of Formula XVI with a compound of Formula XVII to give a compound of Formula XVIII is carried out in a solvent selected from the group consisting of dichloromethane, dichloroethane, acetone, ethyl acetate chloroform, carbon tetrachloride and tetrahydrofuran.
88. The process according to claim 87 wherein the reaction is carried out in dichloromethane.
89. The process according to claim 86 wherein the deprotection of a compound of Formula XVIII to give a compound of Formula XIX is carried out in an alcohol selected from the group consisting of methanol, ethanol, propanol and isopropanol.
90. The process according to claim 89 wherein the deprotection is carried out in methanol.
91. The processes for the preparation of compounds of Formula XII, XV and XIX, substantially as herein described and illustrated by the examples herein.