WO2008099368A1 - Dérivés de macrolides utilisés comme agents antibactériens - Google Patents

Dérivés de macrolides utilisés comme agents antibactériens Download PDF

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Publication number
WO2008099368A1
WO2008099368A1 PCT/IB2008/050568 IB2008050568W WO2008099368A1 WO 2008099368 A1 WO2008099368 A1 WO 2008099368A1 IB 2008050568 W IB2008050568 W IB 2008050568W WO 2008099368 A1 WO2008099368 A1 WO 2008099368A1
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formula
compound
bis
erythromycin
demethyl
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PCT/IB2008/050568
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English (en)
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Anjan Chakrabarti
Yogesh Baban Surase
Balasaheb Kakade
Biswajit Das
Dilip J. Upadhyay
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Ranbaxy Laboratories Limited
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Publication of WO2008099368A1 publication Critical patent/WO2008099368A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention provides macrolide derivatives, which can be used as antibacterial agents.
  • Compounds disclosed herein can be used for treating or preventing conditions caused by or contributed to by gram positive, gram negative or anaerobic bacteria, more particularly against, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxella spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Enterobactericeae or any combination thereof.
  • processes for preparing compounds disclosed herein, pharmaceutical compositions containing compounds disclosed herein, and methods of treating bacterial infections are also provided, and processes for preparing compounds disclosed herein, pharmaceutical compositions containing compounds disclosed herein, and methods of treating bacterial infections.
  • erythromycin A and early derivatives are characterized by bacteriostatic or bactericidal activity for most gram-positive bacteria, atypical pathogens, and many community- acquired respiratory infections and in patients with penicillin allergy.
  • erythromycin A causes numerous drug-drug interactions, has relatively poor absorption, poor local tolerance, loses its antibacterial activity under acidic conditions by degradation and the degraded products are known to be responsible for undesired side effects (Itoh, Z et ah, Am. J. Physiol, 1984, 247:688; Omura, S et ai, J. Med. Chem., 1987, 30: 1942-43).
  • Various erythromycin A derivatives have been prepared to overcome the acid instability and other problems associated with it.
  • Roxithromycin, clarithromycin and azithromycin were developed to address the limitation of erythromycin A. Both clarithromycin and azithromycin were found to be important drugs in the treatment and prophylaxis of atypical mycobacterial infections in patients with HIV.
  • Macrolides were found to be effective drugs in the treatment of many respiratory tract infections. However, increasing resistance among S. pneumoniae has prompted the search for new compounds that retain favorable safety profiles, retain a spectrum of activity and are confined to respiratory pathogens. Consequently, numerous investigators have prepared chemical derivatives of erythromycin A in an attempt to obtain analogs having modified or improved profiles of antibiotic activity. Macro lides exhibit greater efficacy and safety, have broader spectrum of activities, and are particularly effective against resistant pathogens; hence, ketolides have been developed as next generation macrolides.
  • U.S. Patent No. 5,008,249 discloses therapeutic method of stimulating digestive tract contractile motion in mammals with some novel semi-synthetic macrolides.
  • novel macrolide derivatives which can be used as antibacterial agents on a wide variety of gram positive, gram negative or anaerobic bacteria.
  • the present invention provides macroJide derivatives, which can be used in the treatment or prevention of bacterial infection, and processes for the synthesis of these compounds.
  • compositions containing the disclosed compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of bacterial infection are also provided.
  • Formula I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs thereof, wherein: the dashed bond between C-IO and C-I l, depicted by ( — ), represents an optional bond n can be an integer from 2 to 7,
  • Z' can be oxygen or sulfur; V can be -W(CH 2 V ; k can be an integer of from 0 to 6; W can be no atom, -NR 8 - or oxygen; R 8 can be hydrogen or alkyl; alkylene chain of -W(CH 2 ) k - can be optionally substituted with alkyl, hydroxy or alkoxy; R 7 can be alkyl, aryl, heterocyclyl or heteroaryl; R 9 is hydroxyl, alkoxy, -O(CH 2 )iWRb, -0C(0)N(R s )(CH 2 ) d WR b , .NHCO(CH 2 ) h WR b or -OC(O) (CH 2 XWRb (wherein R b is heterocyclyl or heteroaryl; W is as defined earlier; 1 is an integer 0-5, d, h can be integer 2-6 and t can be an integer 1-6) and R 10 is hydrogen or hydroxy protecting group
  • R 3 can be hydrogen, alkyl or -(CH 2 ) r -U; r can be an integer of from 1 to 4; U can be optionally substituted alkenyl or alkynyl;
  • T can be hydrogen, halogen, cyano or alkyl
  • R 4 can be hydrogen, alkyl, -OR 10 , or -NH(CH 2 ) q Ri 7 , wherein Rn is aryl or heteroaryl and q can be an integer between 0 to 4;
  • R 5 can be hydrogen, hydroxyl, -OCORi 7 , -ORi 0 wherein R n and Ri 0 is defined previously;
  • R 6 can be alkyl, alkenyl or alkynyl; further, R 4 and R 5 , together with their carbon atoms to which they are attached (Cn and C] 2 ), can form a group represented by Formula B
  • A can be -O- or -N-, and R 19 is no atom when A is O and M-R20 when A is N wherein M can be alkenyl, -G(CH 2 ) m J, -CR 7 Ry, -NR 7 - or -SO 2 - ⁇ [wherein m can be an integer from 2 to 6, G can be no atom, -CO, -CS, -SO 2 or -NR 7 , J can be no atom or - N((R 7 )(CH 2 ) P - (wherein p can be an integer of from 1 to 4, R 7 and R9 can be independently hydrogen or alkyl)] ⁇ ;
  • R 2 o can be no atom, hydrogen, aryl or heterocyclyl or heteroaryl;
  • X and R 4 can, together with the carbon atoms at the 9- and 11 -position of the erythronolide skeleton, form a group represented by Formula C
  • R 2 i can be alkyl, hydroxyl, alkoxy, phenoxy or aryl; p is defined previously;
  • X and R 3 can, together with the carbon atoms to which they are attached (C9 and C 6 ), form a ring represented by Formula D
  • R 2 1 is defined previously; or, R 3 and R 4 can, together with the carbon atoms at the 6- and 11 -position of the erythronolide skeleton, form a group represented by Formula E
  • R 22 and R 23 are hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
  • R 24 and R25 are independently selected from R 22 , -ORi 0 , SO 2 R 71 NHC(O)R 22 , NHC(O)N(R 3 )(R 22 ), NHSO 2 R 7 or NR 11 Ri 3;
  • Q is -0-, -N(R 22 )-, -OC(O)-CH(R 22 )-, 0-C(O)-N(R 22 ) ⁇ -O-C(O)-O-, N(R 22 )-N
  • erythromycin A 5-O-(3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-6-O-methyl erythromycin A
  • Compound 1 5-O-(3'-N-bis-demethyl-3'-N-aziridin-l-yl)-6-O-methyl erythromycin A
  • Compound 2 5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A
  • Compound 3 5-O-(3 '-N-bis-demethyl-3 '-N-piperidin-l-yl)-6-0-methyl erythromycin A (Compound 4)
  • compositions comprising therapeutically effective amounts of one or more compounds of Formula 1 described herein together with one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • provided herein are methods for treating or preventing conditions caused by or contributed to by bacterial infections comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds of Formula 1 described herein.
  • the condition can be selected from community acquired pneumonia, upper or lower respiratory tract infections, skin or soft tissue infections, acne vulgaris, hospital acquired lung infections, hospital acquired bone or joint infections, mastitis, catheter infection, foreign body, prosthesis infections or peptic ulcer disease.
  • the bacteria) infection can be caused by gram positive, gram negative or anaerobic bacteria.
  • the gram positive, gram negative or anaerobic bacteria can be selected from Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Propionibacterium acnes or Enterobactericeae.
  • the bacterium is cocci.
  • the cocci are drug resistant.
  • метод ⁇ ии comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds of Formula I in combination with one or more therapeutic agents selected from alcohol, benzoyl peroxide, clindamycin, tretinoin, vitamin E, vitamin A and its derivatives, tetracycline, isotretinoin, vitamin C, vitamin D, chaparral, dandelion root, licoric root, Echinacea, kelp, cayenine, sassafras, elder flowers, pantothenic acid, para amino benzoic acid, biotin, cholin, inositol, folic acid, calcium, magnesium, potassium, vitamin B 6 , zinc, carotenoid, azelaic acid, and other therapeutic agents, which can be used to treat acne or condition the skin.
  • one or more therapeutic agents selected from alcohol, benzoyl peroxide, clindamycin, tretinoin, vitamin E, vitamin A and its derivatives
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or -NR n -, wherein R 01 can be hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl, -
  • alkylene refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms and one or more hydrogen can optionally be substituted with alkyl, hydroxy, halogen or oximes. This term can be exemplified by groups such as methylene, ethylene, propylene isomers (e.g., - CH 2 CH 2 CH 2 and -CH(CH 3 )CH 2 ) and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans or geminal geometry.
  • Alkenyl groups can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR o - (wherein R 01 is the same as defined earlier). In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom.
  • alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkoxy, halogen, -CF 3 , cyano, -NRxR 7n , -
  • alkenylene In the event that alkenylene is attached to the heteroatom, the double bond cannot be alpha to the heteroatom.
  • the alkenylene group can be connected by two bonds to the rest of the structure of compound of Formula I.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
  • Alkynyl groups can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR 0T (wherein R 01 is the same as defined earlier). In the event that alkynyl groups are attached to a heteroatom, the triple bond cannot be alpha to the heteroatom.
  • alkynylene refers to a diradical of a triply- unsaturated hydrocarbon, preferably having from 2 to 6 carbon atoms. In the event that alkynylene is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom.
  • the alkenylene group can be connected by two bonds to the rest of the structure of compound of Formula I.
  • substituents such as alkyl, alkenyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano
  • Rx and R x are the same as defined earlier
  • -S(O) m R ⁇ wherein R ⁇ and m are the same as defined earlier
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition.
  • Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, and the like or polycyclic ring structures such as, adamantyl, tricyclo[3.3.1.1]decane, bicyclo[2.2.2]octane, bicyclo[4.4.0]decane, bicyclo- [4.3.0]nonane, bicyclo[3.3.0]octane, bicyclo[2.2.1]heptane and the like,or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like.
  • Cycloalkylalkyl refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier.
  • alkoxy denotes the group O-alkyl, wherein alkyl is the same as defined above.
  • aryl refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups.
  • Aryl groups optionally may be fused with a cycloalkyi group, wherein the cycloalkyi group may optionally contain heteroatoms selected from O, N or S.
  • Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
  • aralkyl refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined below.
  • alkyl groups include benzyl, ethylphenyl, propylphenyl, naphthylniethyl and the like.
  • alkenyl refers to alkenyl-aryl linked through alkenyl (wherein alkenyl is as defined above) portion and the alkenyl portion contains 1 to 6 carbon atoms and aryl is as defined below.
  • aryloxy denotes the group O-aryl, wherein aryl is as defined above.
  • heteroaryl groups includes but are not limited to are benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzo- triazolyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, napthyridinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, purinyl, pyrazinyl, pyrazolin
  • cyclo alkenyl refers to unsaturated carbocyclic ring having three to seven carbon atoms.
  • One or more hydrogen of said alkenyl or alkynyl can be replaced by halogen, hydroxy, cyano, or -NR 5 Rg, wherein R 5 and R 6 are selected from hydrogen and alkyl.
  • Examples of cycloalkenyl include, but are not limited to, cyclopropenyl and cyclobutenyl, and the like. Multiple cyclic structures are also included.
  • halogen or halo refers to fluorine, chlorine, bromine or iodine.
  • halo alkyl refers to alkyl of which one or more hydrogen(s) is/are replaced by halogen.
  • heterocyclyl refers to a non-aromatic monocyclic or polycyclic ring (fused, spiro or bridged) system having 1 to 8 heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, optionally substituted aryl, alkoxy, alkaryl, cyano, nitro, oxo, -CHO, -OCF 3 , -CF 3 , -SCF 3 , carboxy, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
  • Heterocyclyl can optionally include rings having one or more double bonds. Such ring systems can be mono-, bi- or tricyclic. Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups includes but are not limited to are tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl, isoxazolinyl, thiazolinyl, thiazolidinonyl, oxazolinyl or oxazolidinonyl, azabicyclo[3.1.0]hexyl, diazabicyclo[2.2.1]heptyl, azetidinyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, dihydrobenzofuryl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dihydroindolyl, dihydroisoxazolyl, dihydropyridinyl, dioxanyl, dioxolanyl, homop
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are as defined earlier.
  • Heterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are as defined earlier.
  • Alkylcarboxy refers to O C(K))R ⁇ , wherein R ⁇ is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaryl alkyl or heterocyclylalkyl.
  • hydroxy Protecting groups refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Examples of such groups are found in T.W. Greene and P.G.M. Wuts, "Protective groups in organic synthesis", 3 rd Ed, John Wiley and Sons, New York, N. Y., which is incorporated herein by reference.
  • the species of the hydroxy protecting group employed is not so critical so long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • hydroxyl protecting groups include, but are not limited to, acyl, aroyl, alkyl, aryl, butyldiphenylsilyl, methoxymethyl and methylthiomethyl, and the like.
  • polymorphs refers to all crystalline forms and amorphous forms of the compounds described herein, hi addition, some of the compounds described herein may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of this invention.
  • pharmaceutically acceptable salts refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts.
  • examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, sulfuric, phosphoric acid, and the like.
  • organic acids include, but are not limited to aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-liydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic, 2-hydroxyethanesulfonic acid and the like.
  • phrases "pharmaceutically acceptable carriers” is intended to include nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the compounds of present invention include stereoisomers.
  • stereoisomer refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomers and comformational isomers. All such isomeric forms of these compounds are expressly included in the present invention.
  • Each stereogenic carbon may be of the R or S configuration. Although specific compounds may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned as part of the invention.
  • Geometric isomers may occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity.
  • An enantiomer is a stereoisomer of a reference molecule that is the nonsuperimposable mirror image of the reference molecule.
  • a diastereomer is a stereoisomer of a reference molecule that has a shape that is not the mirror image of the reference molecule.
  • An atropisomer is a conformation of a reference compound that converts to the reference compound only slowly on the NMR or laboratory time scale. Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about ⁇ 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 of Formula V can be prepared according to scheme 1.
  • clarithromycin of Formula II can be desmethylated with one or more reagent to give a compound of Formula FII, which can further be bisdemethylated to give a compound of Formula IV.
  • the compound of Formula IV can be reacted with, suitable reagent of Formula X(CF ⁇ ) n X (wherein, X can be halogen and n can be 2-7) to give a compound of Formula V.
  • Clarithromycin of Formula II to give a compound of Formula III can be desmethylated with one or more desmethylating agents, for example, sodium acetate trihydrate in iodine, N-iodo-succinimide iodine in acetic acid, diisopropylazodicarboxylate or mixture(s) thereof in the presence of one or more solvent(s), for example, methanol, dioxane, ethanol, 1-propanol, 2-propanol or mixture(s) thereof,
  • one or more desmethylating agents for example, sodium acetate trihydrate in iodine, N-iodo-succinimide iodine in acetic acid, diisopropylazodicarboxylate or mixture(s) thereof in the presence of one or more solvent(s), for example, methanol, dioxane, ethanol, 1-propanol, 2-propanol or mixture(s) thereof,
  • Compound of Formula HT can be bisdemethyated with sodium metal/iodine to give a compound of Formula IV in presence of one or more solvent(s), for example methanol, ethanol, propanol or mixture(s) thereof.
  • solvent(s) for example methanol, ethanol, propanol or mixture(s) thereof.
  • Compound of Formula IV can be reacted with one or more reagent of Formula X(CH 2 ) n X to give compounds of Formula V in one or more solvent(s), for example, toluene, xylene, dimethylformamide, acetonitrile, methanol, acetone, tetrahydrofuran or mixture(s) thereof, in the presence of one or more inorganic or organic base(s), for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulfate, diisopropyl ethylamine or mixtures thereof.
  • solvent(s) for example, toluene, xylene, dimethylformamide, acetonitrile, methanol, acetone, tetrahydrofuran or mixture(s) thereof
  • solvent(s) for example, toluene, xylene, dimethylformamide, ace
  • compounds of Formula V can be hydrolyzed to give compounds of Formula VI.
  • the compounds of Formula VI can be protected with suitable hydroxyl protecting group of Formula (R p ⁇ ) 2 ⁇ to give compounds of Formula VII (wherein R pT is COPh or COMe)
  • R pT is COPh or COMe
  • compounds of Formula VII can be reacted with triphosgene to form compounds of Formula VIlI, which can be further reacted to give compounds of Formula IX.
  • the compounds of Formula IX can be oxidized to give compounds of Formula X, which can then be reacted with N,N'-carbonyldiimidazole to give compounds of Formula XI
  • the compounds of Formula XI can be reacted with suitable amine R 2O -MNH 2 of Formula XII (wherein M and R2 0 is as defined earlier) to give compounds of Formula XIII.
  • the compounds of Formula XIII can be deprotected to give compounds of Formula XIV.
  • Compounds of Formula V can be hydrolyzed to give compounds of Formula VI in the presence of an acid, for example, hydrochloric acid, sulfuric acid or dichloroacetic acid.
  • Compounds of Formula VI can be hydroxyl protected to give compounds of Formula VII by reacting with Formula (R pr ) 2 O to form compounds of Formula VII in one or more solvent(s), for example, dichloromethane, acetone, dichloroethane, chloroform, carbon tetrachloride, acetonitrile or mixture(s) thereof, in the presence of one or more base(s), for example, triethylamine, potassium carbonate, diisopropylethylamine, pyridine, tributylamine, sodium carbonate, sodium bicarbonate or mixture(s) thereof.
  • solvent(s) for example, dichloromethane, acetone, dichloroethane, chloroform, carbon tetrachloride, acetonitrile or mixture(s) thereof.
  • base(s) for example, triethylamine, potassium carbonate, diisopropylethylamine, pyridine, tributylamine, sodium carbonate, sodium bicarbonate
  • Compounds of Formula VII can be reacted with triphosgene to form compounds of Formula VIII in one or more solvent(s), for example, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or mixture(s) thereof, in the presence of one or more organic base(s), for example, pyridine, triethylamine, diisopropyl ethylamine, tributylamine or mixture(s) thereof.
  • solvent(s) for example, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or mixture(s) thereof.
  • organic base(s) for example, pyridine, triethylamine, diisopropyl ethylamine, tributylamine or mixture(s) thereof.
  • Compounds of Formula VIII can be reacted to give compounds of Formula IX with one or more organic base(s), for example, tetramethyl guanidine, trimethyl amine or mixtures thereof, in one or more solvents), for example, ⁇ N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide or mixtures thereof.
  • organic base(s) for example, tetramethyl guanidine, trimethyl amine or mixtures thereof
  • solvents for example, ⁇ N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide or mixtures thereof.
  • Compounds of Formula IX can be oxidized to give compounds of Formula X with one or more oxidizing agent(s), for example, Dess-Martin periodinane, N- chlorosuccinimide, pyridinium chlorochromate, Swem Oxidation reagent (oxalyl chloride and dimethylsulfoxide), Pfitzner-Moffatt Oxidation reagent (dicyclohexylcarbodiimide and dimethylsulfoxide), Jones Oxidation reagent (chromic acid, aqueous sulfuric acid and acetone), pyridinium dichromate, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or mixtures thereof, N-Chlorosuccinamide can be used in combination with dimethyl sulfide and l-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride can be used in combination with
  • Compounds of Formula X can be reacted with N,N'-carbonyldiimidazole to form compounds of Formula XI in one or more solvent(s), for example, dimethyl formamide, acetonitrile, tetrahydrofuran or mixture(s) thereof, in the presence of one or more base(s), for example, sodium hydride, sodium hydrogen, carbonate, sodium acetate, sodium thiosulfate, potassium carbonate or cesium carbonate.
  • solvent(s) for example, dimethyl formamide, acetonitrile, tetrahydrofuran or mixture(s) thereof
  • base(s) for example, sodium hydride, sodium hydrogen, carbonate, sodium acetate, sodium thiosulfate, potassium carbonate or cesium carbonate.
  • Compounds of Formula XI can be reacted with one or more amine of Formula R 2 O- M-NH 2 to give compounds of Formula XIII in one or more solvent(s), for example, acetonitrile, dimethylformamide, water or combinations thereof.
  • solvent(s) for example, acetonitrile, dimethylformamide, water or combinations thereof.
  • Compounds of Formula XIII can be deprotected to form compounds of Formula XIV in one or more solvent(s), for example, methanol, ethanol, propanol, isopropanol or mixture(s) thereof.
  • solvent(s) for example, methanol, ethanol, propanol, isopropanol or mixture(s) thereof.
  • Compounds of Formula XV, XVI and XVIII can be prepared following scheme 3. Compound of Formula V can be reacted through three pathways. Path A: Compounds of Formula V can be oximated with benzyloxyhydroxylamine hydrochloride to give compounds of Formula XV.
  • Path B Compounds of Formula V can be oximated with hydroxylamine hydrochloride to give an E+Z mixture of compounds of Formula XVI, which can be further purified to its E and Z isomers.
  • Path C Compound of Formula V can be oximated with methoxylamine hydrochloride to give a compound of Formula XVII, which can be hydrolyzed to give compounds of Formula XVIIL
  • the oximation of compound of Formula V with benzyloxyhydroxylamine hydrochloride to give a compound of Formula XV (path A) can be carried out in presence of one or more base(s), for example, triethylamine, potassium carbonate, sodium hydrogen carbonate, cesium carbonate, sodium hydride, pyridine, sodium acetate, sodium thiosulfate, diisopropyl ethylamine or mixture(s) thereof in presence of one or more organic solvent(s), for example, methanol, etlianol, propanol, isopropanol or mixture(s) thereof.
  • base(s) for example, triethylamine, potassium carbonate, sodium hydrogen carbonate, cesium carbonate, sodium hydride, pyridine, sodium acetate, sodium thiosulfate, diisopropyl ethylamine or mixture(s) thereof
  • organic solvent(s) for example, methanol, etlianol, propano
  • the oximation of compound of Formula V with methoxylamine hydrochloride (Path C) to give a compound of Formula XVII can be carried out under similar conditions as conversion of compound of Formula V into compound of Formula XV.
  • the compound of Formula XVII can further be hydrolyzed to give a compound of Formula XVIII in presence of an acid, for example, hydrochloric acid, sulfuric acid or dichloroacetic acid.
  • the compounds disclosed herein are pharmacologically active against gram- positive, gram-negative and anaerobic bacteria and accordingly, are useful as antibacterial agents for treating bacterial infections in a patient in need thereof, for example, in a human or an animal. Because of their antibacterial activity, the compounds described herein may be administered to an animal for treatment orally, topically, rectally, internasally, or by parenteral route.
  • Pharmaceutical compositions disclosed herein comprise pharmaceutically effective amounts of compounds described herein formulated together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Solid form preparations for oral administration include capsules, tablet, pills, powder, granules, cachets and suppositories.
  • active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carrier, for example, sodium citrate, dicalcium phosphate and/or fillers or extenders (for example, starches, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof); binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia or mixtures thereof; disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates, sodium carbonate or mixtures thereof; absorption acceletors, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol mono stearate or mixtures thereof; adsorbants, for example, Ka
  • Capsules, tablets or pills may also comprise buffering agents.
  • Tablets, capsules, pills or granules can be prepared using one or more coatings or shells, for example, enteric coatings or other coatings known to one of ordinary skill in the art.
  • Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • active compounds can be mixed with water or one or more other solvents, solubilizing agents or emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol, fatty acid esters of sorbitan or mixtures thereof.
  • Oral compositions can also include one or more adjuants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents or mixture(s) thereof.
  • aqueous suspensions may be formulated according to methods known to one of ordinary skill in the art, and in particular, using one or more suitable dispersing or wetting and suspending agents.
  • Acceptable vehicles and solvents include one or more of water, Ringer's solution, isotonic sodium chloride or mixture(s) thereof.
  • Dosage forms for tropical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • Active compounds can be admixed under sterile condition with one or more pharmaceutically acceptable carriers and optionally any preservatives or buffers as may be required.
  • Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.
  • compositions may be in unit dosage form.
  • the preparations can be subdivided into unit doses containing appropriate quantities of active components.
  • Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams or any combination and number of such packaged forms.
  • the pieces of sodium metal (16.35 mmol) were dissolved into degassed dry methanol (150 ml) at room temperature( ⁇ 25 0 C) and cooled to 0-5 0 C.
  • 3'-N-desmethyl clarithromycin (2.72 mmol) was dissolved in it and then iodine (13.62 mmol) was added and stirred at about 5 0 C for about 5 hours.
  • This reaction mixture was poured in 25% aqueous ammonium hydroxide and sodium thiosulphate, extracted with methylene chloride.
  • Step 3 Synthesis of 5-O-r3'-N-bis-demethyl-3'-N-pyrrolidin-l-vn- ⁇ -O-methyl erythromycin A
  • Reaction mixture was cooled to room temperature (-25 0 C), filtered through sintered funnel and washed with toluene. The mother liquor was concentrated to minimum volume at about 50 0 C under reduced pressure. The crude compound was dissolved in methylene chloride and washed with water, dried over anhydrous sodium sulphate, filtered and concentrated to give the solid. This was purified by column chromatography using hexane- acetone as eluent to give the title compound.
  • Step 1 Synthesis of 5-CK3 '-N-bis-demethyl-3 '-N-pyrrolidin-1 -vD-3-Q-decladinosyl-6- O-methyl-3 -hydroxy erythromycin A
  • Step 2 Synthesis of 5-O- ⁇ r3'-N-bis-demethyl-3'-N-pyrrolidin-l-ylV2'-O-beEzoyll-3- O-decladinosyl -6-O-methyl-3-hydroxy erythromycin A
  • Step 3 Synthesis of 5-Q-((3'-N-bis-demethyl-3 ⁇ -N- ⁇ )yrrolidin-l-vn-2'-O-benzovU- 11 ,12-dideoxy-3-O-decladinosyl-6-Q-methyl-3-hydroxy-12.11 -(dioxycarbonyl) erythromycin A
  • Triphosgene (3.366 mmol) was added to an ice-cooled solution of compound 5-O- ⁇ (3'- N-bis-demethyl-3'-N-pyrrolidin-l-yl)-2'-O-benzoyl ⁇ -3-O-decladinosyl-6-O-methyl-3- hydroxy erythromycin A (2.8 mmol) in dichloromethane (20 ml) and the reaction mixture was stirred for about 10 min.
  • Step 4 Synthesis of 5-O-ff3'-N4)is-demethyl-3 1 -N-pwolidm-l-ylV2'-O-benzoyli- ll-deoxy-3-O-decladinosv1-6-O-methyl-3-hydroxy-10J l-anhydro erythromycin A
  • 1,1,3,3-Tetramethyl guanidine (5.01 mmol) was added to a solution of compound 5-O- ⁇ (3'-N-bis-demethyl-3'-N-pyrrolidin-l-yl)-2'-O-benzoyl ⁇ -l l,12-dideoxy-3-0- decladinosyl-6-0-methyl-3-hydroxy-12,ll-(dioxycarbonyl) erythromycin A (2.28 mmol) in N,N-dimethylformamide (10 ml) and the reaction mixture was heated at 70-80 0 C for about 6 hours. The reaction mixture was then cooled and poured onto ice-cold water. The separated precipitate was filtered out, dissolved in dichloromethane, washed with water followed by brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound.
  • Step 5 Synthesis of S-O-IG'-N-bis-demethyl-S'-N-pyrrolidin-l-ylW-O-benzovU- 1 l-deoxy-3-O-decladinosyl-6-O-methyl-3-oxo-10,l 1-anhydro erythromycin A Dess-Martin periodinane (3.1 mmol) was added portion wise to a solution of compound 5- O- ⁇ (3 '-N-bis-demethyl-3 '-N-pyrrolidin-l-yl)-2'-O-benzoyl ⁇ -11 -deoxy-3-O-decladinosyl- 6 ⁇ O-methyl-3 -hydroxy- 10,11-anhydro erythromycin A (2.065 mmol) in dichloromethane (15 ml) over a period of 15-25 min at 25 0 C and this reaction mixture was stirred for about 40 min.
  • Step 6 Synthesis of 5-Q-r3 ) -N-bis-demethyl-3'-N-pyrrolidm-l-yl)-l l-deoxy-3-O- decladinosyl-6-O-methyl-3-oxo-10J l-anhydro-12-O-(irnidazole-l-carbonyl) erythromycin A Carbonyl diimidazole (3.43 mmol) was added to a solution of compound 5 -O- ⁇ (3 '-N-bis- demethyl-3 '-N-pyrrolidin-l -yl)-2'-0-benzoyl ⁇ -l l-deoxy-3-0-decladinosyl-6-0-methyl- 3-oxo-10,l 1-anhydro erythromycin A (1.143 mmol) in dimethylformamide (6 ml) and tetrahydrofuran (3 ml) at about -15 0 C and reaction mixture was stirred for about 10 min.
  • Step 7 Synthesis of 5-O- ⁇ '-N-bis-demethyl-3'-N-pyrrolidin-l-ylV2'-O-benzoyl ⁇ - l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-f4-(4-fpyridin- 3-yl)-imidazol-l-yl)-butylimino)1 erythromycin A
  • Step 8 Synthesis of S-O ⁇ '-N-bis-demethyl-S'-N-pyrrolidm-l-ylVll. ⁇ -dideoxy-S-Q- decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-( ' pyridin-3-ylVimidazol-l-yl)- butylimino)] erythromycin A
  • Step I 5-0- f3'-N-bis-demethyl-3'-N- ⁇ yrrolidin-l-ylV6-O-me1hyl erythromycin A 9(EV Oxime
  • Step 2 The above-obtained precipitate (majority of the Z-isomer) was dissolved in ethyl acetate, washed with the aqueous solution of sodium carbonate (pH ⁇ 8.5 to 9). The organic layer was dried over sodium sulphate, filtered and concentrated to get the solid, which further was crystallized from nitromethane to get the Z-isomer of the title compound.
  • Step 1 Synthesis of 5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-Q-methyl erythromycin A 9-(O-methoxy)oxime
  • Step 2 Synthesis of 5-Q-r3'-N-bis-demethyl-3 T -N-azetidin-l-ylV3-O-decladinosyl-6-O- methyl- 3 -hydroxy erythromycin A 9-(O-methoxy)oxime
  • the solution of 5-O-(3'-N-bis-demethyl-3'-N-azetidin-l-yl)-6-O-methyl erythromycin A 9-(O-methoxy)oxime (0.234 mmol) in IN HCl (5 ml) was stirred at room temperature for about 25 min.
  • Example 6 Pharmacological activity Compounds disclosed herein displayed antibacterial activity in vitro especially against strains that are resistant to macrolides either due to efflux (mef strains) or ribosomal modification (erm) strains. These compounds are useful in treating community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections, bone and joint infections, and other bacterial infections, for example, mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease. Minimum inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art.
  • MIC Minimum inhibitory concentration
  • NCEs new chemical entities
  • concentration 1 mg/ml concentration of stock solution of NCEs was prepared in dimethyl- sulfoxide/distilled water/solvent given in National Committee for Clinical Laboratory Standards (NCCLS) manual.
  • NCCLS National Committee for Clinical Laboratory Standards
  • Serial two-fold dilutions of the NCEs and standard antibiotics were prepared as per NCCLS manual.
  • the concentration of stock solution was decided as per the requirement.
  • Preparation of Agar Plates 2 ml of respective NCE or standard antibiotic concentration was added to 18 ml of Molten Mueller Hinton agar to achieve the required range, for example 0.015 ⁇ g/ml - 16 ⁇ g/ml.
  • For fastidious cultures 1 ml of sheep blood was added in Molten Mueller Hinton agar. MHA and MHA with 5% sheep blood plates without any standard antibiotic or
  • NCE for each set were prepared as controls.
  • One MHA and MHA with 5% sheep blood plate without any standard antibiotic or NCE for determining quality check for media was prepared.
  • Teflon template 1 ⁇ L of each culture on each plate was replicated with the help of a replicator
  • the MICs of Quality Control (QC) strains were plotted on the QC chart for agar dilution method. If the MICs were within the range, the results interpreted by comparing MICs of standards against all organisms with those of NCE's.
  • NCCLS disc diffusion assay using 10 ⁇ g 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.
  • Staphylococcus aureus in the range of between about 0.125 ⁇ g/mL to about 32 ⁇ g/mL.
  • the compounds described herein exhibited MIC values against sensitive Streptococcus pneumoniae in the range of between about 0.03 ⁇ g/mL to about 64 ⁇ g/mL.
  • the compounds described herein exhibited MIC values against erythromycin resistant Streptococcus pneumoniae in the range of between about 16 ⁇ g/mL to about 64 ⁇ g/mL.
  • the compounds described herein exhibited MIC values against Haemophilus influenzae in the range of between about 0.06 ⁇ g/mL to about 64 ⁇ g/mL.
  • the compounds described herein exhibited MIC values against sensitive
  • Streptococcus pyogenes in the range of between about 0.06 ⁇ g/mL to about 16 ⁇ g/mL.
  • the compounds described herein exhibited MIC values against erythromycin resistant Streptococcus pyogenes in the range of between about 0.25 ⁇ g/mL to about 64 ⁇ g/mL.
  • the compounds described herein exhibited MIC values against methicillin resistant Staphylococcus aureus s in the range of between about 16 ⁇ g/mL to about 64 ⁇ g/mL.
  • the compounds described herein exhibited MIC values against sensitive Enterococci species in the range of between about 0.125 ⁇ g/mL to about

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Abstract

La présente invention concerne des dérivés de macrolides pouvant être utilisés comme agents antibactériens. Les composés de l'invention peuvent être utilisés pour traiter ou prévenir des affections causées ou induites par des bactéries Gram positives, Gram négatives ou anaérobies, et agissent notamment contre Staphylococcus, Streptococcus, Enterococcus, Haemophilus, Moraxella spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Enterobactericeae ou une combinaison quelconque de celles-ci. L'invention concerne également des procédés de préparation des composés susmentionnés, des compositions pharmaceutiques renfermant ces composés et des méthodes de traitement d'infections bactériennes.
PCT/IB2008/050568 2007-02-15 2008-02-15 Dérivés de macrolides utilisés comme agents antibactériens WO2008099368A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104610402A (zh) * 2014-12-30 2015-05-13 晋江市托美汀生物科技有限公司 一种大环内酯杂质的制备方法
CN107531737A (zh) * 2015-03-25 2018-01-02 哈佛大学的校长及成员们 脱氧糖胺的合成

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016779A1 (fr) * 1997-09-30 1999-04-08 Abbott Laboratories Derives d'erythromycine cetolidee, modifies en 3'-n et substitues en 6-o, possedant une activite antibacterienne
WO2000012521A1 (fr) * 1998-08-26 2000-03-09 Abbott Laboratories Derives 3',3'-n-bis-desmethyl-3'-n-cycloalkyle erythromycine, en tant qu'antagonistes de l'hormone de liberation de la luteostimuline
WO2000012522A1 (fr) * 1998-08-26 2000-03-09 Abbott Laboratories Antagonistes macrolides de l'hormone de declenchement de l'hormone luteinotrophe
WO2007129646A1 (fr) * 2006-05-01 2007-11-15 Taisho Pharmaceutical Co., Ltd. Derive macrolide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016779A1 (fr) * 1997-09-30 1999-04-08 Abbott Laboratories Derives d'erythromycine cetolidee, modifies en 3'-n et substitues en 6-o, possedant une activite antibacterienne
WO2000012521A1 (fr) * 1998-08-26 2000-03-09 Abbott Laboratories Derives 3',3'-n-bis-desmethyl-3'-n-cycloalkyle erythromycine, en tant qu'antagonistes de l'hormone de liberation de la luteostimuline
WO2000012522A1 (fr) * 1998-08-26 2000-03-09 Abbott Laboratories Antagonistes macrolides de l'hormone de declenchement de l'hormone luteinotrophe
WO2007129646A1 (fr) * 2006-05-01 2007-11-15 Taisho Pharmaceutical Co., Ltd. Derive macrolide

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104610402A (zh) * 2014-12-30 2015-05-13 晋江市托美汀生物科技有限公司 一种大环内酯杂质的制备方法
CN104610402B (zh) * 2014-12-30 2017-01-25 晋江市托美汀生物科技有限公司 一种大环内酯杂质的制备方法
CN107531737A (zh) * 2015-03-25 2018-01-02 哈佛大学的校长及成员们 脱氧糖胺的合成
JP2018510878A (ja) * 2015-03-25 2018-04-19 プレジデント アンド フェローズ オブ ハーバード カレッジ デソサミンの合成
EP3277701A4 (fr) * 2015-03-25 2019-03-06 President and Fellows of Harvard College Synthèse de désosamines
US11008358B2 (en) 2015-03-25 2021-05-18 President And Fellows Of Harvard College Synthesis of desosamines

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