WO2005061526A1 - Derives de ketolide 6-11 bicycliques - Google Patents

Derives de ketolide 6-11 bicycliques Download PDF

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Publication number
WO2005061526A1
WO2005061526A1 PCT/US2003/037520 US0337520W WO2005061526A1 WO 2005061526 A1 WO2005061526 A1 WO 2005061526A1 US 0337520 W US0337520 W US 0337520W WO 2005061526 A1 WO2005061526 A1 WO 2005061526A1
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Prior art keywords
aryl
heteroaryl
nhc
alkenyl
substituted
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PCT/US2003/037520
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English (en)
Inventor
Yat Sun Or
Guoqiang Wang
Ly Tam Phan
Deqiang Niu
Nha Huu Vo
Yao-Ling Qiu
Yanchun Wang
Marina Busuyek
Ying Hou
Yulin Peng
Heejin Kim
Tongzhu Liu
Jay Judson Farmer
Guoyou Xu
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Enanta Pharmaceuticals, Inc.
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Application filed by Enanta Pharmaceuticals, Inc. filed Critical Enanta Pharmaceuticals, Inc.
Priority to CNA2003801109976A priority Critical patent/CN1914221A/zh
Priority to PCT/US2003/037520 priority patent/WO2005061526A1/fr
Priority to AU2003295869A priority patent/AU2003295869A1/en
Publication of WO2005061526A1 publication Critical patent/WO2005061526A1/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

Definitions

  • the present invention relates to novel semisynthetic macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to 6-11 bicyclic ketolide derivatives, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
  • Macrolide antibiotics play a therapeutically important role, particularly with the emergence of new pathogens. Structural differences are related to the size of the lactone ring and to the number and nature (neutral or basic) of the sugars. Macrolides are classified according to the size of the lactone ring (12, 14, 15 or 16 atoms).
  • the macrolide antibiotic family (14-, 15- and 16-membered ring derivatives) shows a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability).
  • erythromycin clarithromycin
  • azithromycin are commonly used macrolides.
  • Macrolides possessing a 3- oxo moiety in place of the 3-cladinose sugar are known as ketolides and have shown enhanced activity towards gram-negative bacteria and macrolide resistant gram-positive bacteria.
  • the present invention provides a novel class of C6-C11 bridged erythromycin derivatives which possess antibacterial activity.
  • novel bridged ketolide compounds, or their pharmaceutically acceptable salts, esters or produrugs represented by formula I as illustrated below:
  • A is selected from: a) -OH; b) -OR p , where R p is a hydroxy protecting group; c) -Ri, where R ⁇ is independently selected from:
  • C 1 -C 12 alkyl optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
  • R 3 ⁇ is independently selected from:
  • R 6 is independently selected from: (a) .hydrogen;
  • W is -NR 2 oR 2 ⁇ , where R2 0 and R 2 ⁇ are each independently selected from: a) hydrogen; b) C1-C12 alkyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; c) C2-C12 alkenyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; d) C2-C12 alkynyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;or e) R2 0 and R 2 ⁇ , taken together with the nitrogen atom to which they are attached form a heterocycloalkyl moiety; or
  • Z is selected from: a) hydrogen; b) methyl; or c) halogen; and R 2 ' is hydrogen or R p , where R p , is as previously defined.
  • compositions comprising a therapeutically effective amount of any compound of the present invention in combination with a pharmaceutically acceptable carrier or excipient.
  • methods of treating antibacterial infections in a subject with said pharmaceutical compositions are also disclosed.
  • a first embodiment of the present invention is a compound of formula I as defined herein, or its pharmaceutically acceptable salt, ester, or prodrug.
  • Example 23 Compound of formula I: A and B taken together with the
  • the present invention relates to a method for controlling a bacterial infection in a subject (e.g., mammal, human, horse, dog, cat, fish) comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.
  • the method includes administering to the subject (including a subject identified as in need of such treatment) a therapeutically effective amount of a any compound delineated herein, or any pharmaceutical composition delineated herein to produce such effect.
  • Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal, human, horse, dog, cat, fish) having bacterial infection or disease or disease symptom related to having a bacterial infection (including diseases delineated herein).
  • the method includes administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce such effect. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • the packaged product includes a container, one of the aforementioned compounds in the container, and a legend (e.g., a label or an insert) associated with the container and indicating administration of the compound for treating a disorder associated with bacterial infection, including the diseases delineated herein.
  • a legend e.g., a label or an insert
  • d-C 3 alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals containing between one and three, one and twelve, or one and six carbon atoms, respectively.
  • C ⁇ -C 3 alkyl radicals include methyl, ethyl, propyl and isopropyl radicals
  • -C 6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl radicals
  • examples of -C 12 alkyl radicals include, but are not limited to, ethyl, propyl, isopropyl, n-hexyl, octyl, decyl, dodecyl radicals.
  • substituted alkyl refers to a "C 2 -C12 alkyl” or "C ⁇ -C 6 alkyl” group as previously defined, substituted by independent replacement or one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -C ⁇ -C
  • C2-C12 alkenyl or "C 2 -C 6 alkenyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety containing from two to twelve or two to six carbon atoms having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
  • substituted alkenyl refers to a "C 2 -C 12 alkenyl” or "C 2 -C 6 alkenyl” group as previously defined, substituted by independent replacement or one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -C ⁇ -C ⁇ 2 -alkyl optionally substituted with halogen, C 2 -C ⁇ 2 -alkenyl optionally substituted with halogen, -C 2 -C ]2 -alkynyl optionally substituted with halogen, -NH 2 , protected amino, -NH -C ⁇ -Ci 2 -alkyl, -NH -C 2 -Ci 2 -alkenyl, -NH -C 2 -C ⁇ 2 -alkenyl, -NH -C 2 -C ⁇ 2
  • C 2 -C ⁇ 2 alkynyl or "C 2 -C alkynyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety containing from two to twelve or two to six carbon atoms having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1- propynyl, 1-butynyl, and the like.
  • substituted alkynyl refers to a "C 2 -C ⁇ 2 alkynyl” or "C 2 -C 6 alkynyl” group as previously defined, substituted by independent replacement or one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -C ⁇ -Ci 2 -alkyl optionally substituted with halogen, C 2 -C 12 -alkenyl optionally substituted with halogen, -C 2 -Ci 2 -alkynyl optionally substituted with halogen, -NH 2 , protected amino, -NH -Q-C ⁇ -alkyl, -NH -C 2 -C
  • C]-C 6 alkoxy refers to a C ⁇ -C 6 alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Examples of C C 6 -alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
  • halo and halogen, as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.
  • substituted aryl refers to an aryl group, as previously defined, substituted by independent replacement or one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -C ⁇ -C ⁇ 2 -alkyl optionally substituted with halogen, C 2 -C ⁇ 2 -alkenyl optionally substituted with halogen, -C 2 -Ci 2 -alkynyl optionally substituted with halogen, -NH 2 , protected amino, -NH -C ⁇ -C, 2 -alkyl, -NH -C 2 -C ⁇ 2 -alkenyl, -NH -C 2 -C 12 -alkenyl, -NH -C 3 -C ⁇ 2 -cycloalkyl, -NH -aryl
  • arylalkyl refers to a C ⁇ -C 3 alkyl or C ⁇ -C 6 alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl and the like.
  • substituted arylalkyl refers to an arylalkyl group, as previously defined, substituted by independent replacement or one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to, but not limited to, -F, -CI, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -C ⁇ -Ci 2 -alkyl optionally substituted with halogen, C 2 -C ⁇ 2 -alkenyl optionally substituted with halogen, -C -C ⁇ 2 -alkynyl optionally substituted with halogen, -NH 2 , protected amino, -NH -C ⁇ -Ci 2 -alkyl, -NH -C 2 -Ci 2 -alkenyl, -NH -C 2 -C ⁇ 2 -alkenyl, -NH -C 3 -C ⁇ 2 -cyclo
  • heteroaryl refers to a mono-, bi-, or tri-cyclic aromatic radical or ring having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • substituted heteroaryl refers to a heteroaryl group as previously defined, substituted by independent replacement or one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -C ⁇ -C ⁇ -alkyl optionally substituted with halogen, C - Ci 2 -alkenyl optionally substituted with halogen, -C 2 -C ] 2 -alkynyl optionally substituted with halogen, -NH 2 , protected amino, -NH -C
  • C 3 -C] 2 -cycloalkyl denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • substituted C 3 -C ⁇ 2 -cycloalkyl refers to a C 3 -C) 2 - cycloalkyl group as previously defined, substituted by independent replacement or one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -C ⁇ -C ⁇ 2 -alkyl optionally substituted with halogen, C 2 -C 12 -alkenyl optionally substituted with halogen, -C 2 -C] 2 -alkynyl optionally substituted with halogen, -NH 2 , protected amino, -NH -C ⁇ -C ⁇ 2 -alkyl, -NH -C 2 -C ⁇ 2 -alkenyl, -NH -C 2 -C] 2 -alkenyl, -NH -C 2 -C] 2 -al
  • heterocycloalkyl refers to a non-aromatic 5-, 6- or 7- membered ring or a bi- or tri-cyclic group fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above rings may be fused to a benzene ring.
  • heterocycloalkyl groups include, but are not limited to, [l,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • substituted heterocycloalkyl refers to a heterocycloalkyl group, as previously defined, substituted by independent replacement or one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -C ⁇ -Ci 2 -alkyl optionally substituted with halogen, C 2 - Ci 2 -alkenyl optionally substituted with halogen, -d-C ⁇ -alkynyl optionally substituted with halogen, -NH 2 , protected amino, -NH -C ⁇ -Ci 2 -alkyl, -NH -C 2 -C ⁇ 2 -alkenyl, -NH -C 2 -C ⁇ 2 - alkenyl, -NH -d-C ⁇ -cycloalkyl, -NH -aryl,
  • heteroarylalkyl refers to a C ⁇ -C 3 alkyl or C]-C 6 alkyl residue residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethy], pyrimidinylethyl and the like.
  • substituted heteroarylalkyl refers to a heteroarylalkyl group, as previously defined, substituted by independent replacement or one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, — Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -C ⁇ -Ci 2 -alkyl optionally substituted with halogen, C 2 - C( 2 -alkenyl optionally substituted with halogen, -C 2 -C ⁇ 2 -alkynyl optionally substituted with halogen, -NH 2 , protected amino, -NH -C ⁇ -C ⁇ 2 -alkyl, -NH -C 2 -C ⁇ 2 -alkenyl, -NH -C 2 -C ⁇ 2 - alkenyl, -NH -C 3 -C ⁇ 2 -cycloalkyl,
  • C 1 -C6 alkoxy refers to a Cj-C ⁇ alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Examples of C ⁇ - C ⁇ -alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
  • -C 3 -alkyl-amino refers to one or two C]-C3-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
  • Examples of C]-C3-alkyl-amino include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
  • alkylamino refers to a group having the structure -NH(C ⁇ -C ⁇ 2 alkyl) where C ⁇ -C ⁇ 2 alkyl is as previously defined.
  • dialkylamino refers to a group having the structure -N(C ⁇ -C ⁇ 2 alkyl) (d- C ]2 alkyl), where Cj-C ⁇ 2 alkyl is as previously defined.
  • Examples of dialkylamino are, but not limited to, dimethylamino, diethylamino, methylethylamino, piperidino, and the like.
  • alkoxycarbonyl represents an ester group, i.e., an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like.
  • carboxydehyde refers to a group of formula -CHO.
  • carboxylate refers to a group of formula -C(O)NH(Cr
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxy protecting groups include, but are not limited to, methylthiomethyl, tert-butyl-dimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aromatic group and the like.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethyl silyl, methoxymethyl groups, for example.
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis. 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • protogenic organic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick et al, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
  • an effective amount refers to an amount of a compound which confers a therapeutic effect on the treated subject.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co- usage with other agents.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations. VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d.
  • subject refers to an animal.
  • the animal is a mammal. More preferably the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain two or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- , or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • the compounds of this invention including the compounds of formulae described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof.
  • a "pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention.
  • compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • bacterial infection(s) or "protozoa infections”; includes, but is not limited to, bacterial infections and protozoa infections that occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention.
  • Such bacterial infections and protozoa infections and disorders related to such infections include, but are not limited to, the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.
  • Pseudomonas spp. pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium diptheriae, or Actinobacillus haemolyticum
  • respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae
  • MAC Mycobacterium avium complex
  • gastroenteritis related to infection by Campylobacter jejuni
  • intestinal protozoa related to infection by Cryptosporidium spp.
  • odontogenic infection related to infection by viridans streptococci
  • persistent cough related to infection by Bordetella pertussis
  • gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.
  • atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae; or the like.
  • Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals include, but are not limited to, the following: bovine respiratory disease related to infection by P. haemolytica., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.), dairy cow mastitis related to infection by S. aureus, S. uberis, S. agalactiae, S.
  • dysgalactiae Klebsiella spp., Corynebacterium, or Enterococcus spp.
  • swine respiratory disease related to infection by A. pleuropneumoniae., P. multocida, or Mycoplasma spp.
  • swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella spp., or Serpulina hyodyisinteriae
  • cow footrot related to infection by Fusobacterium spp.
  • cow metritis related to infection by E.
  • cow hairy warts related to Infection by Fusobacterium necrophorum or Bacteroides nodosus cow pink-eye related to infection by Moraxella bovis, cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to infection by E. coli; skin and soft tissue infections in dogs and cats related to infection by S. epidermidis, S. intermedius, coagulase neg. Staphylococcus or P.
  • Alcaligenes spp. Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium spp., Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp., Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosoma spp., Plas,odium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp., Leishmania spp., and Trichomonas spp.
  • Susceptibility tests can be used to quantitatively measure the in vitro activity of an antimicrobial agent against a given bacterial isolate.
  • Compounds were tested for in vitro antibacterial activity by a micro-dilution method.
  • Minimal Inhibitory Concentration (MIC) was determined in 96 well microtiter plates utilizing the appropriate Mueller Hinton Broth medium (CAMHB) for the observed bacterial isolates.
  • Antimicrobial agents were serially diluted (2-fold) in DMSO to produce a concentration range from about 64 ⁇ g/ml to about 0.03 ⁇ g/ml. The diluted compounds (2 ⁇ l/well) were then transferred into sterile, uninoculated CAMHB (0.2 mL) by use of a 96 fixed tip-pipetting station.
  • the inoculum for each bacterial strain was standardized to 5 x 10 5 CFU/mL by optical comparison to a 0.5 McFarland turbidity standard.
  • the plates were inoculated with 10 ⁇ l/well of adjusted bacterial inoculum.
  • the 96 well plates were covered and incubated at 35 +/- 2 C for 24 hours in ambient air environment. Following incubation, plate wells were visually examined by Optical Density measurement for the presence of growth (turbidity). The lowest concentration of an antimicrobial agent at which no visible growth occurs was defined as the MIC.
  • the compounds of the invention generally demonstrated an MIC in the range from about 64 ⁇ g/ml to about 0.03 ⁇ g/ml.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • the term "pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; algin
  • compositions of this invention may be administered orally, parenteral ly, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) abso ⁇ tion accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol, a
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Abso ⁇ tion enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • bacterial infections are treated or prevented in a patient such as a human or other animals by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a “therapeutically effective amount” of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • the compounds of the formulae described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w).
  • such preparations may contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • the pharmaceutical compositions of this invention can be administered orally to fish by blending said pharmaceutical compositions into fish feed or said pharmaceutical compositions may be dissolved in water in which infected fish are placed, a method commonly referred to as a medicated bath.
  • the dosage for the treatment of fish differs depending upon the pu ⁇ ose of administration (prevention or cure of disease) and type of administration, size and extent of infection of the fish to be treated. Generally, a dosage of 5 - 1000 mg, preferably 20 - 100 mg, per kg of body weight of fish may be administered per day, either at one time or divided into several times. It will be recognized that the above- specified dosage is only a general range which may be reduced or increased depending upon the age, body weight, condition of disease, etc. of the fish.
  • CDI for carbonyldiimidazole; dba for dibenzylidene acetone; dppb for diphenylphosphino butane; DBU for l,8-diazabicyclo[5.4.0]undec-7-ene;
  • NMMO for N-methylmo ⁇ holine N-oxide
  • TEA for triethylamine
  • Boc for t - butoxycarbonyl
  • Bz for benzyl
  • a second preferred intermediate for the preparation of compounds represented by formula I is a compound represented by formula X as illustrated below
  • Schemes 1 - 4 describe processes for the preparation of intermediates which are useful in the preparation of compounds according to the invention.
  • erythromycin derivative (1-2) is prepared from erythromycin using the procedures described in U.S. Patents 4,990,602; 4,331,803; 4,680,386; 4,670,549; and European Patent Application EP 260,938.
  • Rn is C ⁇ -Ci 2 -alkyl and Rn is as previously defined.
  • Most palladium (0) catalysts are expected to work in this process.
  • the palladium catalyst can be selected from, but not limited to, the group consisting of palladium (II) acetate, tetrakis(triphenylphospine)palladium (0), tris(dibenzylideneacetone)dipalladium, tetradi(benzylideneacetone)dipalladium and the like. Palladium on carbon and palladium (II) halide catalysts are less preferred than other palladium catalysts for this process.
  • Suitable phosphines include, but are not limited to, triphenylphosphine, bis(diphenylphosphino)methane, bis(diphenylphosphino)ethane, bis(di ⁇ henylphosphino)propane, l,4-bis(diphenylphosphino)butane, bis(diphenylphosphino)pentane, and tri(o-tolyl)phosphine, and the like.
  • aprotic solvent preferably at elevated temperature, for example, at or above 50 °C.
  • Suitable aprotic solvents include, but are not limited to, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, 1,2-dimethoxyethane, methyl-tert-butyl ether, heptane, acetonitrile, isopropyl acetate and ethyl acetate.
  • the most preferred solvents are tetrahydrofuran or toluene.
  • the alkylating agents useful in the processes of the invention are di-carbonates (1-3). Generally, the alkylating agents have the formula (1-3), previously described.
  • the preferred alkylating agents are those wherein R ⁇ 3 is a tert-butyl, isopropyl or isobutyl group.
  • the alkylating reagents are prepared by reaction of a di-ol with a wide variety of compounds for inco ⁇ orating the di-carbonate moiety.
  • the compounds include, but are not limited to, tert- butyl chloroformate, di-tert-butyl dicarbonate, and l-(tert-butoxycarbonyl)imidazole and the reaction is carried out in the presence of an organic or an inorganic base.
  • the temperature of the reaction varies from about -30 °C to about 30 °C.
  • the alkylating reagent is di- tert-butyl dicarbonate.
  • An alternative method of converting the alcohol into the carbonate involves treating the alcohol with phosgene or triphosgene to prepare the chloroformate derivative of the di-ol.
  • the di-chloroformate derivative is then converted into the di-carbonate by the methods described in Cotarca, L., Delogu, P., Nardelli, A., Sunijic, V, Synthesis, 1996, 553.
  • the reaction can be carried out in a variety of organic solvents such as dichloromethane, toluene, diethyl ether, ethyl acetate and chloroform in the presence of a base.
  • Suitable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, dimethylaminopyridine, pyridine, triethylamine and the like.
  • the temperature conditions can vary from 0 °C to about 60 °C.
  • the reaction typically takes about 3 to 5 hours to run to completion.
  • the cladinose moiety of macrolide (1-4) is removed either by mild acid hydrolysis or by enzymatic hydrolysis to give compounds of formula (1-5).
  • Representative acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid.
  • Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol and the like. Reaction times are typically 0.5 to 24 hours.
  • the reaction temperature is preferably -10°C to 80°C Scheme 2
  • simultaneous deprotection of both the oxime and the 2' hydroxyl can be accomplished under a variety of conditions.
  • Conditions for deprotection include, but not limited to, treating with an alcoholic solvent from room temperature to reflux, or treatment with a primary amine, such as butylamine.
  • Alcoholic solvents preferred for the deprotection are methanol and ethanol.
  • Representative acids include, but are not limited to, acetic acid, formic acid, dilute hydrochloric acid, dilute phosphoric acid, dilute sulfuric acid, and the like.
  • Suitable protic solvents include, but are not limited to, mixtures of water and methanol, ethanol, isopropanol, or butanol. The reaction is typically carried out at 50° to 1 10 ° C, preferably for between 1 and 10 hours.
  • compounds of formula (2-3) can be formed directly from compounds of formula (2-1 ) via treatment with TiCl 3 in alcoholic solvents, preferably methanol or ethanol Imines of formula (2-3) can be acylated under basic conditions using a suitable acylating agent in an aprotic solvent.
  • Typical acylating agents include, but are not limited to, acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, and benzyl chloroformate.
  • aprotic solvents are dichloromethane, chloroform, tetrahydrofuran, N- methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide, N,N -dimethylacetamide, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, 1 ,2-dichloroethane, acetonitrile, ethyl acetate, acetone and the like.
  • Aprotic solvents do not adversely affect the reaction.
  • the solvent is selected from dichloromethane, chloroform, N,N -dimethylformamide, tetrahydrofuran, N-methylpyrrolidinone or mixtures thereof.
  • Typical bases include, but are not limited to, pyridine, triethylamine, diisopropyl ethylamine, N-methyl morpholine, N-methyl pyrrolidine, 2,6-lutidine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene.
  • acylating conditions see, for example, T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Synthesis" 3 rd ed., John Wiley & Son, Inc, 1999.
  • R ! 3 is C ⁇ -C
  • Ri i and R p are as previously defined.
  • aprotic solvent preferably at elevated temperature, preferably at or above 50 °C.
  • the most preferred solvents are tetrahydrofuran and toluene.
  • the alkylating agents useful in the process of the invention are the mixed silyl ether carbonates (3-1). Generally, the alkylating agents have the formula (3-1), previously described.
  • the preferred alkylating agents are those wherein Rj 3 is tert-butyl, isopropyl or isobutyl and Rp is tert-butyl dimethyl silyl, triisopropyl silyl, tert-butyl diphenyl silyl or the like.
  • the alkylating reagents of formula (3-1 ) are prepared by reaction of a diol sequentially with a wide variety of compounds for inco ⁇ orating the carbonate moiety, followed by a wide variety of compounds for incorporating the silyl moiety.
  • Alkylating reagents include, but not limited to, tert-butyl chloroformate, di-tert-butyl dicarbonate, and 1- (tert-butoxycarbonyl)imidazole; where as silylating reagents include, but are not limited to tert-butyl dimethyl silyl chloride, tert-butyl dimethyl silyl triflate, tert-butyl dimethyl silyl cyanide, and tert-butyl dimethyl silyl imidazole. Both reactions are carried out in the presence of an organic or an inorganic base. The temperature of the reactions vary from about -30 °C to about 30 °C.
  • the alkylating reagent is di-tert-butyl dicarbonate and the silylating reagent is tert-butyl dimethyl silyl chloride.
  • the free oxime (3-3) is prepared using essentially the same procedure as for the deprotection of oxime (1-4) where R 6 is Ac in Scheme 2.
  • the protecting group (Rp) is then removed from the hydroxyl of the compound of formula (3-4) using the appropriate conditions as outlined in T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Synthesis” 3 rd ed., John Wiley & Son, Inc, 1999.
  • the protecting group is TBS, tetra- «-butyl ammonium fluoride, hydrofluoric acid or trifluoro acetic acid may be used.
  • the primary hydroxyl is converted to the tert-butyl carbonate, and subsequently the 1 1 -hydroxyl group is alkylated by means of a palladium (0) catalyst as described previously. In this way compounds of formula (3-6) can be prepared readily.
  • Compounds according to the invention (5-1) may be prepared by oxidation of the secondary alcohol using Dess Martin periodinane as the oxidant.
  • the reaction is typically run in an aprotic solvent at 0° to 25°C.
  • the reaction time is typically between 1 and 12 hours.
  • the oxidation can be accomplished using pyridinium chlorochromate, sulfur trioxide pyridine complex in dimethyl sulfoxide, tetra- ⁇ -propyl ammonium perruthenate and N-methyl mo ⁇ holine N-oxide, Swern oxidation or the like.
  • pyridinium chlorochromate sulfur trioxide pyridine complex in dimethyl sulfoxide
  • tetra- ⁇ -propyl ammonium perruthenate and N-methyl mo ⁇ holine N-oxide, Swern oxidation or the like.
  • Scheme 5 illustrates another process of the invention for the preparation of compounds according to the invention.
  • Conversion of alkene (6-1) into ketone (6-2) can be accomplished by exposure of the alkene to ozone followed by decomposition of the ozonide with the appropriate reducing agent, as outlined in Scheme 3.
  • the reaction is typically carried out in an inert solvent such as, but not limited to, methanol, ethanol, ethyl acetate, glacial acetic acid, chloroform, methylene chloride or hexanes or mixtures thereof, preferably methanol, preferably at -78° to -20°C.
  • reducing agents are , for example, triphenylphosphine, trimethyl phosphite, , thiourea, and dimethyl sulfide, preferably triphenylphosphine.
  • ketone (6-2) involves dihydroxylation of the alkene followed by diol cleavage.
  • the glycol (6-3) is first prepared by reacting alkene (6- 1) with osmium tetroxide. This reaction can be carried out with stochiometric amounts of osmium tetroxide, or, if an oxidant such as hydrogen peroxide, tert-butyl hydroperoxide, or N-methylmo ⁇ holine-N-oxide is present, with catalytic amounts of osmium tetroxide. These reactions can be carried out in a variety of solvents including: 1 ,4-dioxane, tetrahydrofuran, tert-butanol and diethyl ether, preferably at 0 °C
  • the glycol can be cleaved by a variety of reagents including, but not limited to, periodic acid, lead tetraacetate, manganesedioxide, potassium permanganate, sodium metaperiodate, and N-iodosuccinamide.
  • a variety of solvents can be used.
  • the cleavage reagent is sodium metaperiodate
  • the solvent is preferably a mixture of ethanol, methanol, acetone, or 1 ,4-dioxane and water and the reaction temperature is 0 ° to 25 °C.
  • V O, NH, NOR 6 , NR 12 , NC(O)R, or NC(O)R 2
  • Scheme 6 illustrates the procedure by which compounds of formula (7-1 ) may be converted to compounds of formula (7-2) by treatment with a halogenating reagent.
  • This reagent acts to replace a hydrogen atom with a halogen atom at the C-2 position of the ketolide.
  • Various halogenating reagents may be suitable for this procedure.
  • Fluorinating reagents include, but are not limited to, N-fluorobenzenesulfonimide in the presence of base, 10% F2 in formic acid, 3,5-dichloro-l-fluoropyridinium tetrafluoroborate, 3,5-dichloro-l -fluoropyridinium triflate, (CF3S ⁇ 2)2 ⁇ F, N-fluoro-N- methyl-p-toluenesulfonamide in the presence of base, N-fluoropyridinium triflate, ⁇ - fluoroperfluoropiperidine in the presence of base.
  • Chlorinating reagents include, but are not limited to, hexachloroethane in the presence of base, CF3CF2CH 2 ICI2, SO 2 Cl 2 , SOCl 2 , CF 3 SO 2 Cl in the presence of base, Cl , ⁇ aOCl in the presence of acetic acid.
  • Brominating reagents include, but are not limited to, Br 2 *pyridine » HBr, B ⁇ /acetic acid, N-bromosuccinimide in the presence of base, LDA/BrCH2CH 2 Br, or LDA/CBr 4
  • a suitable iodinating reagent is ⁇ -Iodosuccin imide in the presence of base, or I 2 , for example
  • Suitable bases for the halogenating reactions requiring them are compounds such as alkali metal hydrides, such as ⁇ aH and KH, or amine bases, such as LDA or triethylamine, for example. Different reagents may require different type of base, but this is well known within the art.
  • a preferred halogenating reagent is ⁇ -fluorobenzenesulfonimide in the presence of sodium hydride.
  • Suitable solvents are dimethylformamide, dimethyl sulfoxide, pyrrolidinone and the like.
  • V NOR 6 , NH, O,
  • NC(O)R NC(O)R 2 NR 12
  • acids include, but are not limited to, hydrochloric, phosphoric, sulfuric, p- toluenesulfonic, and pyridinium p-toluene sulfonate.
  • bases that are useful are, for example, triethylamine, pyridine, diisopropylethyl amine, 1 ,5-lutidine, and the like.
  • Appropriate solvents include, but are not limited to, methanol, ethanol, water, tetrahydrofuran, 1 ,2-dimethoxyethane, and ethyl acetate.
  • the reaction is carried out in ethanol using triethylamine as the base.
  • Reaction temperature is generally 25° C and reaction time is 1 to 12 hours.
  • Ketone (6-2) can also be further utilized by conversion into the amine (7-9) via a reductive amination protocol.
  • the ketone is treated with an amine in the presence of a reducing agent to obtain the product amine (7-9).
  • the reaction can be carried out either with or without added acid. Examples of acids that are commonly used include, hydrochloric, phosphoric, sulfuric, acetic, and the like.
  • Reducing agents that effect reductive amination include, but are not limited to, hydrogen and a catalyst, zinc and hydrochloric acid, sodium cyanoborohydride, sodium borohydride, iron petnatcarbonyl, and alcoholic potassium hydroxide. Generally alcoholic solvents are used.
  • the preferred conditions use sodium cyanoborohydride in methanol with added acetic acid.
  • a still further way to functionalize ketone (6-2) is via addition of Grignard reagents to form alcohols of formula (7-8).
  • Scheme 8 depicts this protocol.
  • the requisite Grignard reagents are readily available via the reaction of a variety of alkyl or aryl halides with magnesium under standard conditions (see B.S. Furniss, A.J. Hannaford, P.W.G. Smith, A.R. Tatchell "Vogel's Textbook of Practical Organic Chemistry” 5 th ed., Longman, 1989).
  • the addition is performed in an inert solvent, generally at low temperature.
  • Suitable solvents include, but are not limited to tetrahydrofuran, diethylether, 1 ,4-dioxane, 1 ,2- dimethoxyethane, and hexanes.
  • the solvent is tetrahydrofuran or diethylether.
  • the reaction is run at -78° to 0° C.
  • organometallic reagents examples include, but are not limited to, organo-aluminum, organo-lithium, organo-cerium, organo-zinc, organo-thallium, and organo-boron reagents.
  • organometallic reagents include, but are not limited to, organo-aluminum, organo-lithium, organo-cerium, organo-zinc, organo-thallium, and organo-boron reagents.
  • alcohols of type (7-14) can be prepared by reduction of the corresponding ketone (6-2) under a variety of conditions, (see Hudlicky, M. Reductions in Organic Chemistry, Ellis Horwood Limited: Chichester, 1984).
  • the alcohols thus derived can be further modified to give compounds of type (7-15).
  • Processes to generate compounds of formula (7-15) include, but are not limited to: alkylation of the alcohol with an electrophile or conversion of the alcohol into a leaving group such as a triflate, tosylate, phosponate, halide, or the like followed by displacement with a heteroatom nucleophile (e.g. an amine, alkoxide, sulfide or the like).
  • a heteroatom nucleophile e.g. an amine, alkoxide, sulfide or the like.
  • the glycol (7-5) can be prepared by reacting alkene (6-1 ) with osmium tetroxide. This reaction can be carried out either with stochiometric amounts of osmium tetroxide, or, if a oxidant such as hydrogen peroxide, tert-butyl hydroperoxide, or N-methylmo ⁇ holine-N- oxide are present, with catalytic amounts of osmium tetroxide. These reactions can be run in a variety of solvents including: 1 ,4-dioxane, tetrahydrofuran, tert-butanol and diethyl ether, preferably at 0 °C.
  • glycols thus derived can be further modified to give compounds of type (7-12) by, for instance, selective alkylation of the primary alcohol with an electrophile (see B.S. Furniss, A.J. Hannaford, P.W.G. Smith, A.R. Tatchell "Vogel's Textbook of Practical Organic Chemistry” 5 th ed., Longman, 1989).
  • Epoxides of type (7-10) can be prepared by the conversion of the primary alcohol into a leaving group such as a triflate, tosylate, phosponate, halide, or the like, followed by intramolecular nucleophillic displacement (see Tetrahedron Lett.,, 1983, 661 -664). Epoxides of formula (7-10) can be further funtionalized via ring opening with a variety of nucleophiles. Representative nucleophiles include, but are not limited to, amines, alkoxides, sulfides, organometallic reagents and the like.
  • Reactions can be carried out in the presence or absence of Lewis acid activators such as silver carbonate, silver triflate, boron trifluoride etherate, aluminum trichloride and the like, (see (a) J. Med Chem., 1997, 2762-2769, (b) /. Amer. Chem. Soc, 1999, 10251 - 10263, (c) Tetrahedron Lett. , 2000, 4229-4234)
  • Lewis acid activators such as silver carbonate, silver triflate, boron trifluoride etherate, aluminum trichloride and the like
  • compound (6-1) can undergo a cross metathesis reaction with vinylaromatic derivatives using ruthenium catalysts to give compounds of formula (9-2) (see (a) J. Org. Chem. 2000, 65, 2204-2207; (b) Reviews: Synlett. 1999, 2, 267; (c) Reviews: Ivin, K. J.; Mol, J. C. Olefin Metathesis and Metathesis Polymerization, 2 nd ed.; Academic Press: New York, 1997; (d) J. Org. Chem. 1999, 64, 4798-4816; (e) Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056; (f) Tetrahedron 1998, 54, 4413-4450).
  • R' C1 -C6 alkyl or cycloalkyl, aryl or heteroaryl
  • ketones of formula (6-2) can be transformed into alkenes of formula (9-2) and (8-1 ) via Wittig reaction with the appropriate phosphonium salt in the presence of a base, (see (a) Burke, Tetrahedron Lett., 1987, 4143-4146, (b) Rathke and Nowak, J. Org. Chem., 1985, 2624-2626, (c) Maryanoff and Reitz, Chem. Rev., 1989, 863- 927.
  • vinyl halides of formula (8-1) can be functionalized by Sonogashira coupling with alkynes in the presence of a palladium catalyst, a copper halide and an amine base to give compounds of formula (8-2) (see (a) Sonogashira, Comprehensive Organic Synthesis, Volume 3, Chapters 2,4; (b) Sonogashira, Synthesis 1977, 777.).
  • alkenes of formula (9-2) can be obtained from vinyl halides (8-1) via Suzuki cross coupling with organoboron reagents in the presence of a palladium catalyst and a base, or via Stille cross coupling with organostananes in the presence of a palladium catalyst. ( see (a) Suzuki, J. Organomet. Chem.
  • compounds of the present invention include modification of the 3' N of compounds of the formula (10-1).
  • Compounds of formula (10-2) can be made via the methods delineated in U.S. Patents 6,034,069 and 6,387,885.
  • Titanium trichloride (40 ml, 20% in 3% hydrochloric acid) was added dropwise over 10 minutes to a stirred solution of the compound from Step Id (9.5 g, 1 1.3 mmol) and ammonium acetate (17.4 g, 226 mmol) in 120 ml of methanol at 0°C.
  • the reaction mixture was allowed to warm up to room temperature and stirred over night.
  • Dess-Martin reagent 1.9 g, 4.5 mmol
  • the mixture was stirred at room temperature for 2 hours.
  • the reaction was quenched with sodium bicarbonate (50 ml) and Na 2 S 2 O (2g).
  • the organic phase was separated and washed with brine (50 ml).
  • the solvent was removed under vacuum and the residue was purified on chromatography (hexane:acetone/l : 1 ) to give the title compound (2.0 g).
  • Example 5 81.3 mg (0.32 mmol)of N-phthaloyl-O-quinolin-3-ylmethyl-hydroxylamine was reacted with 12 mg (0.24 mmol) of hydrazine hydrate. Then 7 ⁇ l of glacial acetic acid was added followed by 27 mg (0.04 mmol) of the compound of Example 3. After isolation, 24 mg of the desired product were obtained.
  • Example 4 27 mg (0.04 mmol) of the compound of Example 3, 17 mg (0.08 mmol) of O-(5- pyridin-2-yl-thiophen-2-ylmethyl)-hydroxyl amine and 2.3 ⁇ l (0.04 mmol) of glacial acetic acid were combined in 2 ml of ethanol. After isolation, 22 mg of the desired product were obtained. MS (ESI) m/z 774.48 (M+H) + .
  • Example 12 53.5 mg (0.08 mmol) of the compound of Example 3, 30 ⁇ l (0.24 mmol) of phenethyl amine, 9.2 ⁇ l of glacial acetic acid and 10 mg (0.16 mmol) of sodium cyanoborohydride were combined in 5 ml of methanol. After isolation, 40 mg of the desired product were obtained. MS (ESI) m/z 774.25 (M+H) + .
  • Dess-Martin reagent 3.05 g, 7.2 mmol
  • Example 4 87 mg (0.13 mmol) of the compound of Example 16, 41.5 mg (0.26 mmol) of O- benzyl hydroxylamine and 21 ⁇ l (0.26 mmol) of pyridine were combined in 10 ml of ethanol.
  • Step 18d Compound of formula (3-2)
  • Rp tert-butyl dimethyl silyl
  • R_ H
  • Rn H
  • R,'
  • A is NH ⁇ QLA-Ph
  • B is H
  • L CH?CH 3
  • Z H
  • R2' H
  • B is OH
  • L CH2CH3
  • Z H
  • R2' H
  • Example 3 The compound of Example 3 (70 mg, 0.1 mmol) was treated with benzylmagnesium bromide (0.85 M in THF, 0.6 mL, 0.5 mmol) as described in Example 29. After the same work up, the crude mixture was purified by flash chromatography (Si ⁇ 2 , CH 2 CI 2 containing 5% 2M ammonia solution in methanol) to provide the title compound (12 mg, 18 %).
  • MS (ESI) m/z 761 (M+H) + ⁇ C-NMR (100 MHz, CDCl 3 ): ⁇ 205.7, 186.3, 179.5, 169.8, 136.3, 131.0, 128.1 , 126.5, 101.8,
  • Example 3 The compound of Example 3 (70 mg, 0.1 mmol) was treated with phenethylmagnesium bromide (1.0 M in THF, 0.5 mL, 0.5 mmol) as described in Example
  • Example 3 The compound of Example 3 (70 mg, 0.1 mmol) was treated with phenylmagnesium bromide (1.0 M in THF, 0.5 mL, 0.5 mmol) as described in Example 29. After the same work up, the crude mixture was purified by flash chromatography (SiO , CH 2 C1 2 containing 5%
  • the compound from Example 29 50 mg, 0.07 mmol), iodobenzene (32 mg, 0.15 mmol), Pd(OAc) 2 (2.5 mg), (o-Tolyl) 3 P (10 mg) and triethyl amine (0.1 mL, excess) were dissolved in 3 ml CH 3 CN and the solution was degassed at -40°C.
  • reaction mixture was warmed to room temperature under nitrogen, heated at 50°C for 1 hour, and then left at 80°C for 12 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO 3 , and dried over anhydrous Na 2 SO 4 .
  • the solvent was evaporated and the residue was purified by flash chromatography (SiO 2 , CH 2 C1 2 containing 5% 2M ammonia solution in methanol) to provide the title compound (40 mg, 76 %).
  • Example 24 The compound from Example 24 (15 mg, 0.02 mmol) was hydrogenated under 1 atm H 2 over Pd-C in ethanol at room temperature for 24 hours. The solvent was evaporated under vacuum. Purification by flash chromatography (SiO 2 , CH 2 C1 2 containing 5% 2M ammonia solution in methanol) gave the title compound (13.2 mg, 88 %).
  • A is (CH,) 3 -Ph
  • B is H
  • R,' H
  • Example 35 The compound of Example 35 (15 mg, 0.02 mmol) was hydrogenated under H 2 (30 psi) over Pd-C in ethanol at room temperature for 12 hours. The solvent was evaporated under vacuum. Purification by flash chromatography (SiO 2 , CH 2 C1 2 containing 5% 2M ammonia solution in methanol) gave the title compound (7.0 mg, 50 %).
  • Example 35 213 mg (0.3 mmol) of the compound of Example 1 , and 103 ⁇ L (0.6 mmol) of
  • Example 35 142 mg (0.2 mmol) of the compound of Example 1 , and 71 ⁇ L (0.4 mmol) of 4- bromodiphenyl ether were reacted to give the the title compound.
  • a solution of the compound from Step 44f (0.15 mmol at most) in CH 2 C1 (3.0 mL) was treated with Dess-Martin periodinane (108 mg, 0.25 mL) for 4.5 hours at room temperature.
  • the resulting mixture was partitioned between ethyl aceate and aqueous saturated NaHCO 3 :Na 2 S 2 ⁇ 3 /3: l .
  • the organic phase was washed with water and brine.
  • Step 45a Compound of formula 6-3: V is N-Ac.
  • THF (4.0 mL) was treated with sodium bis(trimethylsilyl)amide (1.0 M in THF, 1.00 mL, 1.00 mmol) at -78° C under nitrogen. The mixture was stirred at -70— 60°C for 1 hour before a solution of the compound from Step 45b (127 mg, 0.18 mmol) in THF (5.0 mL) was added.
  • reaction mixture was warmed to room temperature over 1 hour and stirred at that temperature for 5 hours.
  • the mixture was then partitioned between ethyl acetate and water.
  • Step 46a Fluorination of the 3 position.
  • the fluorinated compound from Step 46a is refluxed in MeOH according to the procedure set forth in Example 2 to yield the 2' hydroxy compound.
  • Step 46c Ozonolysis The compound prepared in Step 46b is converted to the title compound via ozonolysis according to the procedure elucidated in Example 3.
  • substituted hydroxylamines used in the following examples are either commercially available or can be made from readily-available starting materials via synthetic methods well known by one with ordinary skill in the art.
  • the Examples described in Table Al are single isomers of the E designation, which are separated from the E/Z mixture via silica chromatography or HPLC.
  • substituted hydroxylamines used in the following examples are either commercially available or can be made from readily-available starting materials via synthetic methods well known by one with ordinary skill in the art.
  • Table A2 The Examples described in Table A2 are single isomers of the E designation, which are separated from the E/Z mixture via silica chromatography or HPLC.
  • substituted hydroxylamines used in the following examples are either commercially available or can be made from readily-available starting materials via synthetic methods well known by one with ordinary skill in the art.
  • Table B The Examples described in Table B comprise mixtures of E and Z isomers, which can be separated via silica chromatography or HPLC.
  • the Examples described in Table Bl are single isomers of the E designation, which are separated from the E/Z mixture via silica chromatography or HPLC.
  • Table B2 The Examples described in Table B2 are single isomers of the Z designation, which are separated from the E/Z mixture via silica chromatography or HPLC.
  • bromo compounds used to form the following examples are commercially available or can be made from readily-available starting materials via synthetic methods well known by one with ordinary skill in the art.
  • Table C comprise mixtures of E and Z isomers, which can be separated via silica chromatography or HPLC.
  • the amino compounds used to form the following examples are commercially available or can be made from readily-available starting materials via synthetic methods well known by one with ordinary skill in the art.

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Abstract

Cette invention se rapporte à des composés représentés par la formule (I), où à des sels, esters, ou promédicaments de ces composés, acceptables sur le plan pharmaceutique, qui possèdent des propriétés antibactériennes. Cette invention se rapporte également à des compositions pharmaceutiques comprenant ces composés, en vue de leur administration à un sujet nécessitant un traitement antibiotique, ainsi qu'à des procédés pour traiter une infection bactérienne chez un sujet, en lui administrant une composition pharmaceutique comprenant ces composés. Cette invention concerne en outre un procédé de fabrication de ces composés.
PCT/US2003/037520 2003-11-20 2003-11-20 Derives de ketolide 6-11 bicycliques WO2005061526A1 (fr)

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CNA2003801109976A CN1914221A (zh) 2003-11-20 2003-11-20 6－11双环酮大环内酯衍生物
PCT/US2003/037520 WO2005061526A1 (fr) 2003-11-20 2003-11-20 Derives de ketolide 6-11 bicycliques
AU2003295869A AU2003295869A1 (en) 2003-11-20 2003-11-20 6-11 bicyclic ketolide drivatives

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010539191A (ja) * 2007-09-17 2010-12-16 エナンタ ファーマシューティカルズ インコーポレイテッド ６，１１−架橋ビアリールマクロライド

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4921839A (en) * 1987-02-24 1990-05-01 Beecham Group P.L.C. Erythromycin a 11,12-carbonate 9-oxime derivatives
US5202434A (en) * 1991-04-05 1993-04-13 Merck & Co., Inc. 8a-aza-8a-homoerythromycin lactams
US5441939A (en) * 1994-03-04 1995-08-15 Pfizer Inc. 3"-desmethoxy derivatives of erythromycin and azithromycin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4921839A (en) * 1987-02-24 1990-05-01 Beecham Group P.L.C. Erythromycin a 11,12-carbonate 9-oxime derivatives
US5202434A (en) * 1991-04-05 1993-04-13 Merck & Co., Inc. 8a-aza-8a-homoerythromycin lactams
US5441939A (en) * 1994-03-04 1995-08-15 Pfizer Inc. 3"-desmethoxy derivatives of erythromycin and azithromycin

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010539191A (ja) * 2007-09-17 2010-12-16 エナンタ ファーマシューティカルズ インコーポレイテッド ６，１１−架橋ビアリールマクロライド
JP2015017139A (ja) * 2007-09-17 2015-01-29 エナンタ ファーマシューティカルズ インコーポレイテッド ６，１１−架橋ビアリールマクロライド

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