EP1027360A2 - 3-descladinose 6-o-substituierte erythromycin derivate - Google Patents

3-descladinose 6-o-substituierte erythromycin derivate

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Publication number
EP1027360A2
EP1027360A2 EP98941119A EP98941119A EP1027360A2 EP 1027360 A2 EP1027360 A2 EP 1027360A2 EP 98941119 A EP98941119 A EP 98941119A EP 98941119 A EP98941119 A EP 98941119A EP 1027360 A2 EP1027360 A2 EP 1027360A2
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EP
European Patent Office
Prior art keywords
substituted
compound
formula
heteroaryl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP98941119A
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English (en)
French (fr)
Inventor
Yat Sun Or
Leping Li
Michael J. Rupp
Daniel T. Chu
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Abbott Laboratories
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Abbott Laboratories
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Publication of EP1027360A2 publication Critical patent/EP1027360A2/de
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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
    • 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

  • This invention relates to novel semi- synthetic macrolides having antibacterial activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treatment. More particularly, the invention relates to 3- descladinose 6-O-substituted erythromycin derivatives and methods for preparing them, compositions containing these compounds, and a method of treating bacterial infections with such compositions.
  • erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
  • Morimoto et al. describes the preparation of 6-O-methyl erythromycin A in J. Antibiotics 37:187 (1984). Morimoto et al. further discloses 6-O-alkyl erythromycin A derivatives in J. Antibiotics, 43: 286 (1990) and in European Patent Application 272,110, published June 22, 1988. European Patent Application 215,355, published March 28, 1987, discloses 6-O-loweralkyl erythromycins as stimulants of gastrointestinal contractile motion. United States Patent 5,444,051 discloses 6-O-substituted-3-oxoerythromycin A derivatives in which the substituents are selected from alkyl, -CONH2, -CONHC(O) alkyl and - CONHSO2alkyl.
  • PCT application WO 97/10251 published March 20, 1997, discloses 6-O- methyl 3-descladinose erythromycin derivatives
  • PCT application WO 97/17356 published May 15, 1997, discloses 3-deoxy-3-descladinose erythromycin derivatives.
  • PCT appUcation WO 92/09614, published June 11, 1992 discloses tricyclic 6-O-methyl erythromycin A derivatives. Certain intermediates to the present invention are disclosed in U.S. Patent AppUcation Serial Number 08/888,350.
  • the present invention provides a novel class of 3-descladinose 6-O-substituted erythromycin derivatives which possess antibacterial activity.
  • X is selected from the group consisting of
  • R 1 is as previously defined and R 5 and R 6 are each independently selected from the group consisting of (a) hydrogen,
  • C6-alkyl, or R 7 and R 8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionaUy contain a hetero function selected from the group consisting of -O-, -NH-, -N(C ⁇ -C6-alkyl-)-, N(aryl)-, -N(aryl-C ⁇ -C6-alkyl-)-, -N(substituted-aryl-C ⁇ -C6-alkyl-)-, -N(heteroaryl)-, - N(heteroaryl-C ⁇ -C6-alkyl-)-, -N(substituted-heteroaryl-C ⁇ -C6-alkyl-)-, and -S- or -S(O) n -, wherein n is 1 or 2,
  • R w is selected from the group consisting of
  • Ci- -alkyl optionally substituted with one or more substituents selected from the group consisting of (a) aryl,
  • R 9 is selected from the group consisting of:
  • RP is hydrogen or a hydroxy protecting group
  • R is selected from the group consisting of
  • R 10 is C ⁇ -C3-alkyl or aryl substituted C ⁇ -C3-alkyl, or heteroaryl substituted C ⁇ -C3-alkyl,
  • R 1 J and R 12 are independently selected from hydrogen, C ⁇ -C3-alkyl, C ⁇ -C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl,
  • R 13 and R 14 are selected from the group consisting of (i) hydrogen, (n) C ⁇ -Ci2-alkyl, (in) substituted C ⁇ -Ci2-aUcyl, (iv) C ⁇ -Ci2-alkenyl, (v) substituted C ⁇ -Ci2-alkenyl,
  • R 13 and R 14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (i) halogen, (ii) hydroxy,
  • U' is hydrogen or in compounds of formula (II) and (III) U' is taken together with U to form a double bond between the carbon atoms to which they are attached.
  • the present invention also provides pharmaceutical compositions which comprise a therapeuticaUy effective amount of a compound as defined above in combination with a pharmaceuticaUy acceptable carrier.
  • the invention further relates to a method of treating bacterial infections in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeuticaUy effective amount of a compound as defined above.
  • a first embodiment of the invention is a compound having the formula (I) as described above.
  • Representative compounds of the invention having formula (I) are those selected from the group consisting of: Compound of Formula (I): R is allyl, RP is H, X is O, U is OH;
  • R is allyl, RP is benzoyl, X is O, U is OH;
  • Compound of Formula (I): R is -CH2-CH CH2-(3-quinolinyl), RP is H, X is O, U is O- acetyl;
  • a second embodiment of the invention is a compound having the formula (Et) as described above.
  • a preferred embodiment is a compound of formula (II) wherein W is absent and R is H.
  • Representative compounds of the invention having formula (II) are those selected from the group consisting of:
  • U is O-(3,5-diphenylpyridinecarboxyl);
  • U is O-(3,4,5-trimethoxybenzoyl);
  • U is O-(2-methylbutanoyl);
  • U is O-(l,l-dimethylethoxycarbonyl
  • U is O-(2-furancarboxoyl);
  • U is O-methanesulfonyl
  • Compound of Formula (II): R is -CH 2 -CH CH 2 -(3-quinolinyl), RP s H, X is O, W is absent, R is H, U is O-CO-NH-(4-fluorophenyl);
  • Compounds of Formula (II): R is -CH 2 -CH CH2-(3-quinolinyl), RP s H, W is absent, R w is
  • Compounds of Formula (II): R is -CH2-CH CH2-(3-quinolinyl), RP is H, W is absent, R w is H, U is O-S(O)2-CH 2 -CH 2 -S-phenyl;
  • Compound of Formula (II): R is -CH2-CH CH2-(3-quinolinyl), RP is H, W is absent, R w is
  • U is O-(4-morphotinecarbonyl);
  • U is O-pyrroUdinylcarbonyl
  • Compound of Formula (II): R is -CH2-CH CH 2 -(3-quinolinyl), RP is H, U and U' taken together are double bond, W is absent, R w is H;
  • W is absent, R w is H, R is -CH 2 CH(O), RP is acetyl, U is OH;
  • W is absent, R w is H, R is -CH2CH 2 NHCH 2 -phenyl, RP is acetyl, U is OH;
  • W is absent, R is H, R is -CH 2 CH NHCH 2 CH 2 -phenyl, RP is acetyl, U is OH;
  • a compound having the formula (HI) as described above is a compound having the formula (HI) as described above.
  • Representative compounds of the invention having formula (HI) are those selected from the group consisting of:
  • Compound of Formula (III): R is -CH2-CH CH 2 -(3-quinolinyl), RP is H, U is OH, U' is H;
  • W is absent, R is H, R is -CH2CH 2 NHCH2-phenyl, RP is H, U is OH;
  • a fourth embodiment of the invention is a compound having the formula (IV) as described above.
  • Representative compounds of the invention having formula (IV) are those selected from the group consisting of:
  • Compound of Formula (IV): R is -CH2-CH CH 2 -(3-quinolinyl), RP is H, U is O-C(O)- phenyl;
  • the compounds of the present invention include both those in which the group at the 3- position is the natural (3S) isomer and those in which the group at the 3-position is non-natural (3R) isomer.
  • Step (b) optionally treating the compound of Step (a) with a hydroxy protecting reagent to give a compound having the formula
  • step (e) the reagent L-T-R 1 is selected from the group consisting of:
  • step (e) the reagent L-T-R 1 in the presence of base is replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.
  • Another aspect of the invention is a process for preparing a compound of formula (II)
  • R is as defined above and Rp is a hydroxy protecting group to give a compound having the formula &
  • step (j) optionally treating the compound from step (i), wherein W is absent and R w is H and U is 4"-hydroxy protected cladinose, with an alkylating agent selected from the group consisting of R w -halogen to give a compound of formula (16A) wherein W is absent, U is 4"-hydroxy protected cladinose, and R is as defined above;
  • step (s) the reagent L-T-R 1 in the presence of base is replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.
  • Another aspect of the invention is a process for preparing a compound of formula (HI)
  • U is hydroxy and U' is hydrogen, optionally followed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3- oxo group to give the non-natural (3R) isomer;
  • step (c) treating a compound selected from the group 15A and 15B of step (b) with ethylenediamine to give a bicychc carbamate compound selected from the group consisting of compounds 21A, wherein U is O-4"-acetylcladinose, and 21B. wherein U and U' form a double bond, respectively,
  • step (d) treating the a compound selected from the group 21A and 21B of step (c) with dilute acid to give a compound selected from the group consisting of compounds 22A and 22B, respectively,
  • U is O-4"-acetylclad ⁇ nose
  • 22B, U and U' form a double bond
  • step (e) hydrolyticaUy removing the cladinose moiety from a compound (22A) from step (d) by treatment with acid, reprotecting the 2' hydroxyl group by treatment with a hydroxy protecting reagent, optionally followed by converting the compound having the natural (3S) isome ⁇ c configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non- natural (3R) isomer, to give a compound having the formula (23P),
  • step (f) optionaUy treating the 3-hydroxy group of the product compound from step (e) having the formula (III) wherein R is as defined previously and RP is H, U is hydroxy and U' is hydrogen with base and a reagent L-T-R 1 , wherein L is a leaving group and T and R l are as defined previously, to give a compound of formula (III) wherein RP is H, U is -O-T-R* and U' is hydrogen;
  • step (i) optionally treating the 3-hydroxy group of the product compound from step (e) having the formula (III) wherein R is as defined previously and RP is H, U is hydroxy and U' is hydrogen sequentially with an excess of NaH, CS2 and CH3I to form a 3-O-xanthate intermediate which is treated with Bu3SnH in the presence of a radical initiator to give the desired compound of formula (HI) wherein RP, U and U' are hydrogen; and
  • step (f) the reagent L-T-R 1 is selected from the group consisting of:
  • step (f) the reagent L-T-R 1 is in the presence of base is replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.
  • Another aspect of the invention is a process for preparing a compound of formula (IV)
  • Rp, R and U are as defined above; the method comprising:
  • R is as defined above and Rp is a hydroxy protecting group, with carbonyldiimidazole and sodium hexamethyldisilazide for a short time at about -30 °C to give a compound having the formula 29
  • Step (b) optionally treating a compound having the formula J_4 as shown in Step (a) with an alkati metal hydride and a carbonylating agent selected from the group consisting of phosgene, diphosgene and triphosgene under anhydrous conditions with careful control of the amount of base present in order to prevent base catalyzed decarboxylation to give a compound having the formula 29 as shown in Step (a);
  • a carbonylating agent selected from the group consisting of phosgene, diphosgene and triphosgene
  • step (e) the reagent L-T-R 1 is selected from the group consisting of: (e-i) halogen-C(O)-R l ;
  • step (e) the reagent L-T-R 1 is in the presence of base is replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.
  • Another aspect of the invention is a process for preparing a compound of formula (V)
  • Rp, R and U are as defined above, the method comprising:
  • R is as defined above and Rp is a hydroxy protecting group, with a reagent selected from the group consisting of (i) formaldehyde in the presence of an acid and (ii) chloroiodomethane in the presence of base, to give a compound having the formula 33
  • Step (b) treating hydrolytically with acid a compound from Step (a) having the formula 33. to give a compound of formula (V) wherein U is hydroxy and Rp is a hydroxy protecting group, optionally foUowed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3- hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer;
  • optionaUy treating a compound of formula (V) wherein U is hydroxy and RP is a hydroxy protecting group (a compound from Step (b)) with an excess of NaH in an aprotic solvent followed by reaction of the intermediate anion with CS2 and CH3I to form a xanthate intermediate which is then treated with Bu3SnH under an inert atmosphere in the presence of a catalytic amount of a suitable radical initiator to give the desired compound of formula (V) wherein U is hydrogen and RP is a hydroxy protecting group;
  • R t are as previously defined, and L is a suitable reactive leaving group to give the desired compound of formula (V) wherein U is O-T-R 1 and RP is a hydroxy protecting group;
  • step (d) the reagent L-T-R 1 is selected from the group consisting of:
  • step (d) the reagent L-T-R 1 in the presence of base is replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.
  • C ⁇ -C3-alkyl saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, one and six, and one and twelve carbon atoms, respectively, by removal of a single hydrogen atom.
  • C ⁇ -C3-alkyl radicals include methyl, ethyl, propyl and isopropyl
  • examples of C ⁇ -C6-alkyl radicals include, but are not Hmited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl
  • Examples of Ci- Ci2-alkyl radicals include, but are not hmited to, all the foregoing examples as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-docecyl.
  • C1-C6- alkoxy refers to an C ⁇ -C6-alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Examples of -C6- alkoxy but are not hmited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neo-pentoxy and n-hexoxy.
  • C ⁇ -Ci2-alkenyl denotes a monovalent group derived from a hydrocarbon moiety containing from two to twelve carbon atoms and having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
  • C ⁇ -Ci2-alkynyl refers to a monovalent group derived from a hydrocarbon containing from two to twelve carbon atoms and having at least one carbon- carbon triple bond by the removal of a single hydrogen atom.
  • Representative alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
  • alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1 ,2- ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like.
  • C ⁇ -C3-alkylamino 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-alkylamino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
  • oxo denotes a group wherein two hydrogen atoms on a single carbon atom in an alkyl group as defined above are replaced with a single oxygen atom (i.e. a carbonyl group).
  • 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, heteroaryl compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • aryl refers to a mono- or bicycUc carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • C3-Ci2-cycloalkyl denotes a monovalent group derived from a monocyctic or bicycUc saturated carbocycUc ring compound by the removal of a single hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.
  • alkylamino refers to a group having the structure -NHR' wherein R' is alkyl, as previously defined, Examples of alkylamino include methylamino, ethylamino, iso- propylamino and the like.
  • dialkylamino refers to a group having the structure -NR'R" wherein R' and R" are independently selected from alkyl, as previously defined. Additionally, R' and R" taken together may optionaUy be -(CH2)k- where k is an integer of from 2 to 6. Examples of dialkylamino include, dimethylamino, diethylaminocarbonyl, methylethylamino, piperidino, and the like.
  • haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, 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.
  • thioalkoxy refers to an alkyl group as previously defined attached to the parent molecular moiety through a sulfur atom.
  • carboxydehyde refers to a group of formula -CHO.
  • carboxy refers to a group of formula -CO2H.
  • carboxyamide refers to a group of formula -CONHR'R" wherein R' and R" are independently selected from hydrogen or alkyl, or R' and R" taken together may optionally be -(CH2)k- where k is an integer of from 2 to 6.
  • heteroaryl refers to a cyclic aromatic radical 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, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • heterocycloalkyl refers to a non-aromatic partially unsaturated or fuUy saturated 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which may include aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring.
  • heterocycloalkyl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocycles include, but are not hmited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazoUdinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • heterocycloalkyl rings considered useful in preparing compounds of the invention include: 3-methyl-4-(3-methylphenyl)piperazine, 3-methylpiperidine, 4-(bis-(4- fluorophenyl)methyl)piperazine, 4-(diphenylmethyl)piperazine, 4-(ethoxycarbonyl)piperazine, 4-(ethoxycarbonylmethyl)piperazine, 4-(phenylmethyl)piperazine, 4-( 1 -phenylethyl)piperazine, 4-( 1 , 1 -dimethylethoxycarbonyl)piperazine, 4-(2-(bis-(2-propenyl)amino)ethyl)piperazine, 4- (2-(diethylamino)ethyl)piperazine, 4-(2-chlorophenyl)piperazine, 4-(2-cyanophenyl)piperazine, 4-(2-ethoxyphenyl)piperazine, 4-(2-ethylphenyl)piperazine, 4-(2-flu
  • “Hydroxy-protecting group” refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable.
  • the use of hydroxy-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf., for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991).
  • hydroxy-protecting groups include, but are not hmited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsUyl, ethers such as methoxymethyl, and esters including acetyl benzoyl, and the like.
  • ketone protecting group refers to an eashy removable group which is known in the art to protect a ketone group against undesirable reactions during synthetic procedures and to be selectively removable.
  • the use of ketone-protecting groups is weU known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf, for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991).
  • ketone-protecting groups include, but are not hmited to, ketals, oximes, O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, 1- isopropoxycyclohexyl oxime, and the like.
  • protected-hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsUyl, triethylsilyl, methoxymethyl groups, for example.
  • 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 weU 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 solubtiity 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. ⁇ , in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
  • substituted aryl refers to an aryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C ⁇ -C3-alkyl, C ⁇ -C6-alkoxy, C ⁇ -C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, aUcoxycarbonyl and carboxamide.
  • any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group.
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • substituted heteroaryl refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C ⁇ -C3-alkyl, C ⁇ -C6-alkoxy, C ⁇ -C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group.
  • substituted heterocycloalkyl refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C ⁇ -C3-alkyl, C ⁇ -C6-alkoxy, -C6- alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group. Numerous asymmetric centers may exist in the compounds of the present invention.
  • the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be present.
  • pharmaceuticalaUy 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. describe pharmaceutically acceptable salts in detail in Pharmaceutical Sciences.
  • 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.
  • suitable organic acid examples include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic 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,
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceuticaUy acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as hahde, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • esters which hydrolyze in vivo and include those that break down readUy in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxyhc acids, particularly aUcanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems. Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design. American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • Antibacterial Activity Representative compounds of the present invention were assayed in vitro for antibacterial activity as foUows: Twelve petri dishes containing successive aqueous dilutions of the test compound mixed with 10 mL of sterihzed Brain Heart Infusion (BHI) agar (Difco 0418-01-5) were prepared. Each plate was inoculated with 1:100 (or 1:10 for slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 different microorganisms, using a Steers replicator block. The inoculated plates were incubated at 35- 37 °C for 20 to 24 hours. In addition, a control plate, using BHI agar containing no test compound, was prepared and incubated at the beginning and end of each test.
  • BHI Brain Heart Infusion
  • An additional plate containing a compound having known susceptibility patterns for the organisms being tested and belonging to the same antibiotic class as the test compound was also prepared and incubated as a further control, as well as to provide test-to-test comparability. Erythromycin A was used for this purpose.
  • MIC minimum inhibitory concentration
  • 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.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid fiUer, diluent, encapsulating material or formulation auxUiary 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; ceUulose and its derivatives such as sodium carboxymethyl ceUulose, ethyl ceUulose and ceUulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oU, cottonseed oil; safflower oil; sesame oU; olive oil; corn oU and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic sahne; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non- toxic
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenteraUy, intracisternally, intravaginally, intiaperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • Liquid dosage forms for oral administration include pharmaceuticaUy 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, solubiUzing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oUs (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, terrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as
  • 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 sterUe injectable solution, suspension or emulsion in a nontoxic parenterally acceptable dUuent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionaUy 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 injec tables.
  • 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.
  • 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.
  • 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 siUcic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrohdinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain sUicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a simUar type may also be employed as fiUers in soft and hard- fiUed 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 sheUs such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionaUy contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentiaUy, in a certain part of the intestinal tract, optionaUy, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fiUers in soft and hard- fiUed gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and sheUs such as enteric coatings, release controlUng coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert dUuents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalhne ceUulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentiaUy, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentiaUy, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which 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 pharmaceuticaUy 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, sUicones, 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, sUicones, 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, sihcic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionaUy contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controUed delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controUed by either providing a rate controUing 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 lower mammal by administering to the patient a therapeuticaUy effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeuticaUy 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 appUcable to any medical treatment. It wiU be understood, however, that the total daily usage of the compounds and compositions of the present invention wiU be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient wiU 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 coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the total daUy dose of the compounds of this invention administered to a human or other mammal 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 2000 mg of the compound(s) of this invention per day in single or multiple doses.
  • Scheme 1 Ulustrates the preparation of compounds 6, which are useful as starting materials for the preparation of compounds of formulas (I) - (V) of the invention.
  • the preparation of protected erythromycin A is described in the following United States patents, US 4,990,602; US 4,331,803, US 4,680,368, and US 4,670,549 which are incorporated by reference. Also incorporated by reference is European Patent Application EP 260,938.
  • the C-9-carbonyl group of compound 1 is protected as an oxime
  • R 1 is defined previously and R 5 and R 6 are each independently selected from the group consisting of (a) hydrogen, (b) unsubstituted C ⁇ -Ci2-alkyl, (c) Ci- Ci2-alkyl substituted with aryl, and (d) C ⁇ -Ci2-alkyl substituted with substituted aryl, or R 9 and R 10 taken together with the carbon to which they are attached form a C3-Ci2-cycloalkyl ring).
  • An especiaUy preferred carbonyl protecting group V is O-(l-isopropoxycyclohexyl) oxime.
  • the 2'- and 4"-hydroxy groups of 2 are protected by reaction with a suitable hydroxy protecting reagent, such as those described by T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Son, Inc., 1991, which is incorporated by reference.
  • Hydroxy protecting groups include, for example, acetic anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, or a trialkylsUyl chloride in an aprotic solvent.
  • aprotic solvents are dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone, dimethylsulfoxide, diethylsulfoxide, 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, acetonitrile, ethyl acetate, acetone and the like.
  • Aprotic solvents do not adversely affect the reaction, and are preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N- methyl pyrrolidinone or a mixture thereof. Protection of 2'- and 4"-hydroxy groups of 2 may be accomplished sequentially or simultaneously to provide compound 3 where RP is a hydroxy protecting group. A preferred protecting group RP is trimethylstiyl.
  • RP is a hydroxy protecting group.
  • a preferred protecting group RP is trimethylstiyl.
  • the 6-hydroxy group of compound 3 is then alkylated by reaction with an alkylating agent in the presence of base to give compound 4.
  • Alkylating agents include alkyl chlorides, bromides, iodides or alkyl sulfonates.
  • alkylating agents include allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, ⁇ -bromo-p-tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, l-bromo-2-pentene, 3-bromo-l-propenyl phenyl sulfone, 3-bromo-l-trimethylsilyl-l-propyne, 3-bromo-2-octyne, l-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane
  • alkyl sulfonates examples include: allyl O-tosylate, 3-phenylpropyl-O-trifluoromethane suffonate, n-butyl -O-methanesulfonate and the like.
  • solvents used are aprotic solvents such as dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrroUdone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like.
  • aprotic solvents such as dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrroUdone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone
  • Examples of the base which can be used include potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tert-butoxide, potassium isobutoxide and the like.
  • Schemes 7-9 below describe procedures for further elaboration of the 6-position moiety of the compounds of the invention.
  • the deprotection of the 2'- and 4"-hydroxyl groups is then carried out according to methods described in literature, for example, by Greene and Wuts (op. cit.).
  • the deoximating agent examples include inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate, potassium metabisulfite and the like, and inorganic nitrite salts such as sodium nitrite or potassium nitrite.
  • the solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or a mixture of one or more of the mentioned solvents and the like.
  • the deoximation reaction is more conveniently carried out in the presence of an organic acid such as formic acid, acetic acid and trifluoroacetic acid.
  • the amount of acid used is from about 1 to about 10 equivalents of the amount of compound 5 used.
  • the deoximation is carried out using an organic acid such as formic acid in ethanol and water to give the desired product 6.
  • Scheme 2 illustrates the conversion of intermediate 6 to compounds of formula (I) of the invention.
  • the cladinose moiety of macrolide 6 is removed either by mtid aqueous acid hydrolysis or by enzymatic hydrolysis to give 7.
  • Representative acids include dUute 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 to 35 °C.
  • Compound 7 is converted to ____ which is protected at the 2'-hydroxy position, by treatment with a suitable hydroxy protecting reagent such as acetic anhydride, benzoic anhydride, benzyl chloroformate or trialkylsUyl chloride in an aprotic solvent, as defined previously, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N- methyl pyrrohdinone or a mixture thereof.
  • Preferred protecting groups are trimethylsUyl, acetyl and benzoyl.
  • Compounds 7 and 8 are compounds of formula (I).
  • Compound 8 is then treated with an excess of NaH at from 0 to -30°C under an inert atmosphere in an aprotic solvent such as THF, foUowed by reaction of the intermediate anion with CS2 and CH3I at about -5 to 10°C, to form the xanthate intermediate 9, which is then treated with about 1.1-1.3 equivalents of Bu3SnH under an inert atmosphere in the presence of a catalytic amount of AIBN or other suitable radical initiator, in a solvent suitable for a free radical reaction, such as benzene or toluene, for example, at reflux conditions to afford the desired 3-deoxy compound JO, which is a compound of formula (I) wherein U is hydrogen.
  • an aprotic solvent such as THF
  • compound 8 is reacted with the appropriate acyl hatide having the formula halogen-C(O)-R l or an acyl anhydride having the formula O-(C(O)-R t )2 in an aprotic solvent and in the presence of a tertiary organic amine base, such as triethylamine, dimethylaminopyridine, N-methylmorpholine, N- methylpyrrohdine, or the like, or an inorganic bases such as Na2CO3, K2CO3, NaH, KH, LiH, or the like, at a temperature from about 0 °C to about 150 °C.
  • a tertiary organic amine base such as triethylamine, dimethylaminopyridine, N-methylmorpholine, N- methylpyrrohdine, or the like
  • an inorganic bases such as Na2CO3, K2CO3, NaH, KH, LiH, or the like
  • compound 8_ is reacted with the appropriate carbonate compound of the formula R t -O-C(O)-O- R l under similar conditions.
  • T is -CH2-, having the formula O-CH2-R 1
  • compound 8 is reacted with a strong base, such as an alkali metal hydride or hexamethyldisilazane, for example, followed by reaction with the appropriate alkyl halide having the formula halogen-CH2-R l .
  • a strong base such as an alkali metal hydride or hexamethyldisilazane
  • T is -C(S)-S-, having the formula O-C(S)-S-R l
  • compound 8 is reacted with a strong base, such as an alkali metal hydride or hexamethyldisilazane, for example, followed by reaction with CS2 then the appropriate organohalide having the formula halogen-R 1 .
  • a strong base such as an alkali metal hydride or hexamethyldisilazane, for example
  • compound 8 may be reacted with a carbonyl compound such as carbonyl diimidazole or carbonyl bis(benzotriazole) followed by reaction of the intermediate thus formed with an amine having the formula N(R S )H-R l to prepare the desired compound.
  • compound 8. is reacted with the appropriate acid anhydride compound of the formula O-(S(O) n -R l )2 i n an aprotic solvent and in the presence of a tertiary organic amine base, such as triethylamine, dimethylaminopyridine, N-methylmorpholine, N- methylpyrrolidine, or the like, or an inorganic bases such as Na2CO3, K2CO3, NaH, KH, LiH, or the like, at a temperature from about 0 °C to about 150 °C.
  • a tertiary organic amine base such as triethylamine, dimethylaminopyridine, N-methylmorpholine, N- methylpyrrolidine, or the like, or an inorganic bases such as Na2CO3, K2CO3, NaH, KH, LiH, or the like
  • compound 8. is reacted with 3,4-dihydro-2H-py ⁇ an in an aprotic solvent in the presence of a acid catalyst.
  • the 2' hydroxy protecting group of compounds JO and JJ. may optionaUy be removed by standard methods to give the desired unprotected compounds of formula (I).
  • RP is an ester such as acetate or benzoate
  • the compound may be deprotected by treatment with methanol or ethanol.
  • RP is a trialkylsilyl group
  • the compound may be deprotected by treatment with fluoride in THF or acetonitrile.
  • compounds wherein R 1 is other than H may be prepared by initial formation of the unsubstituted oxime as described above foUowed by reaction with R l X' wherein X' is a suitable leaving group such as halogen.
  • R l X' wherein X' is a suitable leaving group such as halogen.
  • the 9-substitutent is an amino group of the formula HNR 7 R 8 wherein R 7 and R 8 are as previously defined.
  • Scheme 3 iUustrates the methods used to prepare compounds of formula (II) of the invention.
  • the 6-O- substituted compound 6 may be converted to a hydroxy-protected compound 7 and treated with acid to remove the cladinose to give compound _[ as described in scheme 2.
  • Compound 8 may be treated by oxidation of the hydroxyl group to an oxo group at the 3-position followed by selective reduction at the 3-position to give the compound 8 . wherein the hydroxyl group is in the non-natural (3R form).
  • compound 8 may be treated by oxidation of the hydroxyl group to an oxo group at the 3-position foUowed by non-selective reduction to give the compound having 3- and 9-position hydroxyl groups, followed by selective re-oxidation of the 9-OH group to the oxo group, to give the compound 8 wherein the hydroxyl group is in the non-natural (3R form). In these cases, it may be necessary to separate the various isomers by chromatography, as is well know in the art.
  • the isomerization procedures may be interjected into any of the schemes below to give the desired compound having the non-natural (3R) hydroxyl group at the 3-position.
  • compound 6 may be converted to a hydroxy-protected compound J4 with a suitable hydroxy protecting group by the procedures referenced previously.
  • Compounds 8 and 14 can then treated with an excess of sodium hexamethyldisilazide or a hydride base in the presence of carbonyldiimidazole in an aprotic solvent for 8 to 24 hours at about -30 °C to room temperature to give compounds 15B and 15A. respectively.
  • the hydride base may be, for example, sodium hydride, potassium hydride, or lithium hydride, and the aprotic solvent may be one as defined previously.
  • the reaction may require coohng or heating from about -20°C to about 70°C, depending on the conditions used, and preferably from about 0°C to about room temperature.
  • the reaction requires about 0.5 hours to about 10 days, and preferably about 1-5 days, to complete. Portions of this reaction sequence follow the procedure described by Baker et al, J. Org. Chem., 1988, 53, 2340, which is incorporated herein by reference.
  • treating 8 with a sulfonylating agent such as methanesulfonyl anhydride, methanesulfonyl chloride, ethanesulfonyl chloride, or p-toluenesulfonyl chloride, in a aprotic solvent with stirring at from about 0°C to ambient temperature for about 1 to about 24 hours to provide a selectively 3-O-sulfonated compound (not shown), followed by treatment of this sulfonated compound with a hydride base in the presence of carbonyldiimidazole in an aprotic solvent gives the desired 2,3 unsaturated compound 15B.
  • a sulfonylating agent such as methanesulfonyl anhydride, methanesulfonyl chloride, ethanesulfonyl chloride, or p-toluenesulfonyl chloride
  • U is 0-4" -acetylcladinose 15A.
  • U is 0-4 "-acetylcladinose:
  • U and U' form a double bond 1 B.
  • U and U' form a double bond
  • Compound JJ. may then be treated by the procedure described previously for the conversion of compound 8 to 10 to give the desired compound JJ . of formula (II) wherein U and U' are H.
  • Compound 17 may also be treated by the procedure described previously for the conversion of compound 8 to JJ, to give the desired compound JJ) of formula (II) wherein U is -O-T-R 1 and U' is H.
  • Optional deprotection of the 2'-hydroxy group from compounds 16B, 17, 18 and ⁇ _9_, by the methods described earlier provides the desired unprotected analogous compounds of formula (II).
  • Scheme 4 describes the preparation of compounds of formula (HI).
  • Compound 15A or 15B wherein U is the -O-4" -acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, is treated with ethylenediamine 20 in a suitable solvent such as aqueous acetonitrile, DMF or aqueous DMF, to give the bicyclic carbamate compound 21A or 21B, wherein U is the -O-4" -acetylcladinose moiety or U and U' are taken together to form a double bond, respectively.
  • Compound 21A or 21B is then cyclized by treatment with dUute acid, such as acetic acid or HCl in a suitable organic solvent such as ethanol or propanol, to give compound 22A or 22B.
  • dUute acid such as acetic acid or HCl
  • suitable organic solvent such as ethanol or propanol
  • the cladinose moiety is then removed from compound 22A, wherein U is an -O-4"- acetylcladinose moiety, to give compound 23, which is a compound of formula (III) wherein U is hydroxy and U' is H.
  • Compound 23 is then converted to compounds 24 and 25 by the procedures described in Scheme 3 for conversion of compound J 7 to compounds JJ and 19, respectively.
  • Compounds 22B, 23, 24 and 25 are embodiments of the compounds of formula (HI). Optional deprotection of these compounds may be performed by methods described previously.
  • Compound 27 is then converted to compounds 28 or 29 by the procedures described in Scheme 3 for conversion of compound Y ⁇ to compounds JJ, and JJ), respectively.
  • Compounds 28, and 29 are additional embodiments of the compounds of formula (IV). Optional deprotection of the these compounds is by methods described previously.
  • Compound 3_1 is then converted to compounds 32 or 33 by the procedures described in Scheme 3 for conversion of compound J to compounds JJ and 19, respectively.
  • Compounds 32 and 33 . are additional embodiments of the compounds of formula (V). Optional deprotection of the these compounds is by methods described previously.
  • the double bond of the allyl compound can be (a) catalytically reduced to give the 6-O-propyl compound 35; (b) treated with osmium tetroxide to give the 2,3-dihydroxypropyl compound 36 which in turn may be functionalized, such as by esterification with an acylating agent such as an acyl hahde or acyl anhydride, at each oxygen atom to give 37; (c) oxidized with m- chloroperoxybenzoic acid in an aprotic solvent to give the epoxy methyl compound 8 which can be opened with nucleophihc compounds, for example, amines or N-containing heteroaryl compounds, to give compounds with N-containing side chains 39; (d) oxidized under Wacker conditions as described by Henry in "Palladium Catalyzed Oxidation of Hydrocarbons", Reidel Publishing Co., Dordrecht, Holland (1980), to give the 6-O-CH 2 -C(O)-CH 3 compound 40; and (e) o
  • Reaction of the oxime 43 with dusopropyl carbodiimide in an aprotic solvent in the presence of CuCl gives the nitrile 45.
  • Reaction of 34 with an aryl hahde under Heck conditions in the presence of (Pd(II) or Pd(O), phosphine, and amine or inorganic base gives 46.
  • Reduction of the double bond in 46, for example using H2 and palladium on carbon gives 47.
  • Scheme 8 Ulustrates an alternate procedure for preparing compounds of formula (IT) wherein R is substituted alkenyl.
  • the 6-O-allyl erythromycin compound 16A. wherein R is allyl is converted to the compound 48 by removing the cladinose and protecting the free 3- hydroxyl group as described in earlier Schemes.
  • compound 16A wherein R is allyl
  • 6-O-(substituted alkenyl) compound of formula 50 is converted to the 6-O-(substituted alkenyl) compound of formula 50 by reaction with an aryl hahde, a substituted aryl hahde, an heteroaryl halide or substituted heteroaryl halide under Heck conditions with (Pd(II) or Pd(O), phosphine, and amine or inorganic base, as just described.
  • Compound 50 may then be converted to the desired compound 4J wherein R is substituted alkenyl, by removing the cladinose and optionally deprotecting as described in eartier Schemes. These procedures may be employed whenever any other modification of the 6-O- substitutent is also performed, such as with the modifications described in Schemes 7 or 9.
  • the desired 6-O-substituted compound may be prepared by chemical modification of an initially prepared 6-O-propargyl compound.
  • compound 51 which iUustiates a compound of the invention where R is propargyl and M' represents the macrolide ring system, can be further derivatized.
  • the triple bond of compound 51 can be treated with an aryl halide, a substituted aryl halide, a heteroaryl halide or substituted heteroaryl hahde in the presence of Pd(triphenylphosphine)2Cl2 and Cul in the presence of an organic amine, such as triethylamine, to give the compound 52.
  • Compound 52 can be further selectively reduced to the corresponding s-olefin compound 53 by catalytic hydrogenation in ethanol at atmospheric pressure in the presence of 5% Pd BaSO4 and quinoline (Rao et al, J. Org. Chem., (1986), 1: 4158-4159).
  • Compound 51 may also be treated with a boronic acid derivative HB(OR zz ), wherein R zz is H or Cj-Cio-alkyl, in an aprotic solvent at 0 °C to ambient temperature to give compounds 54, which are then treated with Pd(triphenylphosphine)4 and an aryl hahde, a substituted aryl halide, an heteroaryl halide or substituted heteroaryl hahde under Suzuki reaction conditions to give compounds 55.
  • Compound 5 _ may also be treated with N- halosuccinimide in acetic acid to give compounds 56.
  • Z' is 4"-acetyl-cladinose
  • Example 1 Compound of Formula (I): R is allyl. RP is H. X is O. U is OH
  • Step la Compound 4 from Scheme 1: V is N-O-(l-isopropoxycyclohexyl). R is aUyl. RP is trimethylsilyl. To a 0 °C solution of 2',4"-to-O-trimethylsUylerythromycin A 9-[ ⁇ -(l- isopropoxycyclohexyl)oxime (1.032 g, 1.00 mmol), prepared according to the method of U.S. Pat. No. 4,990,602 in 5 mL of DMSO and 5 mL of THF was added freshly distilled aUyl bromide (0.73 mL, 2.00 mmol).
  • Step lb Compound 5 from Scheme 1 : V is NOH. R is aUyl.
  • Step lc Compound 6 from Scheme 1; R is allyl
  • the compound resulting from step 1 b ( 1.225 g) in 16 mL of 1 : 1 ethanol-water was treated with NaHSO3 (700 mg) and formic acid ( 141 ⁇ L) at 86 °C for 2.5 hours.
  • the reaction mixture was allowed to cool to ambient temperature, diluted with 5-6 mL of water, basified with 1 N NaOH to pH 9- 10 and extracted with ethyl acetate.
  • the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo.
  • Step Id Compound of Formula (I): R is allyl. RP is H. X is O, U is OH To a suspension of the compound from step lc (7.73 g, 10.0 mmol) in ethanol (25 mL) and water (75 mL) was added aqueous 1 M HCl (18 mL) over 10 minutes. The reaction mixture was stirred for 9 hours at ambient temperature, then was left standing in the refrigerator overnight. Aqueous 2 M NaOH (9 mL, 18 mmol) was added, which resulted in the formation of a white precipitate. The mixture was dhuted with water and filtered. The solid was washed with water and dried under vacuum to give the des-cladinosyl compound £7 from Scheme 2) (3.11 g).
  • 3-bromoquinoline 6.1 1 mL, 45 mmol
  • paUadium acetate 1.03 mg, 4.5 mmol
  • tri-(o-tolyl)phosphine 2.74 mg, 9.0 mmol
  • triethylamine 8.36 mL, 60 mmol.
  • Step 5b Com p ound of Formula (I): R is-C ⁇ -CH ⁇ CHo-G-quinolinyl). RP is H. X is O. U is O-(4-methoxy)benzoyl Methanol (6 mL) was added to the reaction mixture from Step 5a, and the mixture was heated at reflux for 5 hours to remove the 2'-benzoyl protecting group. At the completion of the reaction, the solvents were removed by evaporation, and the reside was purified by flash chromatography on silica gel eluted with dichloromethane/methanol/ammonium hydroxide (10:1:0.05 to 20:1:0.05) to give the title compound (105 mg, 85%) as a white foam. MS (ESI) m/z 877 [M+H] + , HRMS: calcd for C49H69N2O11, 877.4851; found, 877.4845.
  • RP is H.
  • X is_O.
  • U is O-CO-
  • Step 8b Compound 15A of Scheme 3, R is allyl, RP is acetyl. U is 4"-acetylcladinose
  • Step 8c Compound 16A of Scheme 3.
  • R is allyl.
  • RP is acetyl, U is 4"-acetylcladinose,
  • Step 8e 100 mg, 0.124 mmol was heated in refluxing methanol (2 mL) for 3 hours to remove the 2'-acetyl protecting group. At the completion of the reaction, the solvents were removed by evaporation, and the reside was purified by flash chromatography on sUica gel eluted with dichloromethane/methanol ammonium hydroxide (10:1:0.05 to 20: 1:0.05) to give the title compound (90 mg, 94.8%).
  • Examples 28-36 Following the procedures of Example 27, except substituting the isocyanate reagent shown in the table below for the phenyl isocyanate of Example 27, the compounds of Examples 28-36 with U as shown in the table below were prepared.
  • RP is H.
  • W is absent.
  • R w is H.
  • Step 50a Compound of Formula (IV).
  • RP is acetyl.
  • U is 4"- acetylcladinose
  • Step 50b Com p ound of Formula (IV).
  • RP is acetyl.
  • U is OH
  • Step 52a Compound 21 A of Scheme 3, R is allyl, RP is acetyl
  • acetonitrile 40 mL
  • THF 4 mL
  • ethylenediamine 2.67 mL, 39.1 mmol
  • the solution was stirred under nitrogen overnight at room temperature, then heated at 80 °C for 3 hours. Solvents were removed by evaporation, and the residue was taken up in ethyl acetate. The solution was washed with NaHCO ⁇ , brine, dried and concentrated.
  • Step 52b Compound 22A of Scheme 3, R is allyl. RP is H
  • Step 52a The compound from Step 52a was redissolved in a mixture of ethanol/acetic acid (40 ⁇ L/0.4 mL), and the mixture was heated at reflux for 5 hours. Ethanol was evaporated off, residue was taken up in dichloromethane, which was then washed with aqueous sodium bicarbonate, brine, dried and concentrated.
  • Step 52c Compound 22A of Scheme 3, R is allyl, RP is acetyl
  • RP is H.
  • U is OH.
  • U' is H
  • RP is H.
  • U is O-C(O)- phenyl Following the C3-O-acylation and C2'-deacetylation procedures described in Example 10, except substituting benzoic anhydride for the acetyl anhydride thereof, the title compound was prepared in two-steps. MS (ESI) m/z 897 [M+H]+.
  • RP is H.
  • W is NH.
  • R w is H.
  • U is OH
  • Step 56a Compound 16A of Scheme 3.
  • R is aUyl.
  • RP is acetyl.
  • U is 4" -acetylcladinose,
  • W is NH.
  • R is H
  • RP is H.
  • U is H.
  • U' is H A sample of the intermediate descladinose compound wherein RP is acetyl from
  • Example 57 is treated with tri(n-butyl)tin hydride under nitrogen atmosphere and a catalytic amount of AEBN in toluene at reflux to give the 2'acetylated intermediate.
  • the 2'-acetyl group is removed by treatment overnight with hot methanol to give the title compound.
  • RP is H.
  • W is absent, R w is
  • Example 61 Compound of Formula (IP: W is absent. R is H. R is -O ⁇ CHfO). RP is H, U is OH
  • the compound from Example 8, Step 8b, is treated with ozone under N2 followed by treatment with dimethylsulfide and triphenylphosphine. The intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on sihca gel to give the title compound.
  • W is absent.
  • R w is H.
  • R is -C ⁇ C ⁇ NHC ⁇ -phenyl.
  • RP is H.
  • U is OH
  • Example 63 Compound of Formula (ID: W is absent.
  • R w is H, R is -C C NHC CIh-phenvL RP is
  • RP is H.
  • U is OH
  • the compound from Example 61 is treated with 3-phenyl-l-propylamine in dry dichloromethane in the presence of molecular sieves (4A).
  • the resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2.
  • the intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on silica gel to give the title compound.
  • Example 65 Compound of Formula (II): W is absent.
  • R w is H.
  • R is -CH2CH2NHCH2CH2CH2CH2- phenyl.
  • RP is H.
  • U is OH
  • the compound from Example 61 is treated with 4-phenyl-l-butylamine in dry dichloromethane in the presence of molecular sieves (4A).
  • the resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2.
  • the intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on silica gel to give the title compound.
  • Example 66 Compound of Formula (IP: W is absent.
  • R is H, R is -CH2CH2NHCH2CH2CH2- (3-quinolvP.
  • RP is H.
  • U is OH
  • Example 67 Compound of Formula (ID: W is absent.
  • R is H.
  • R is -C ⁇ CTbNHC ⁇ G-quinolyl).
  • RP is
  • W is absent.
  • R w is H.
  • U is
  • Example 61 The compound from Example 61 is treated with O-phenylhydroxylamine-HCl in dry dichloromethane in the presence of triethylamine.
  • the intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on silica gel to give the title compound.
  • the title compound was prepared from the compound of Example 61 (and O- benzylhydroxylamine-HCl in dry dichloromethane in the presence of triethylamine.
  • the intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on sihca gel to give the title compound.
  • Example 70 is H.
  • U is OH
  • the title compound was prepared from the compound of Example 61 and O-(4- nitrobenzyl)hydroxylamine-HCl in dry dichloromethane in the presence of triethylamine.
  • the intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on sihca gel to give the title compound.
  • Example 73 Compound of Formula (II): W is absent.
  • R w is H.
  • RP is H.
  • U is ⁇ H
  • the title compound was prepared from the compound of Example 62 and O-(3- quinolyl)methylhydroxylamine in dry dichloromethane in the presence of triethylamine.
  • the intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on silica gel to give the title compound.
  • Example 74 Compound of Formula (HP: W is absent.
  • R is H.
  • R is -CH2CH ⁇ ).
  • RP is H.
  • U is ⁇ H
  • Example 52 The compound from Example 52 is treated with ozone under N2 followed by treatment with dimethylsulfide and triphenylphosphine.
  • the intermediate is treated with ethanoUc HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on silica gel to give the title compound.
  • Example 75 Compound of Formula ( IID: W is absent.
  • R w is H.
  • R is -C CIftNHCIfr-phenyl.
  • RP is H.
  • Example 74 The compound from Example 74 is treated with O-phenylhydroxylamine-HCl in dry dichloromethane in the presence of triethylamine.
  • the intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on silica gel to give the title compound.
  • Example 77 Compound of Formula (IV): W is absent.
  • R w is H.
  • R is -CH CH(O).
  • RP is H.
  • U is OH
  • the compound from Example 50 is treated with ozone under N2 followed by treatment with dimethylsulfide and triphenylphosphine.
  • the intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on silica gel to give the title compound.
  • W is absent.
  • R is H, R is -C ⁇ C ⁇ NHC ⁇ -phenyl.
  • RP is H.
  • Example 77 The compound from Example 77 is treated with benzylamine in dry dichloromethane in the presence of molecular sieves (4A). The resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanoUc HCl, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
  • Example 77 The compound from Example 77 is treated with O-phenylhydroxylamine-HCl in dry dichloromethane in the presence of triethylamine.
  • the intermediate is treated with ethanolic HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on sUica gel to give the title compound.
  • Example 80 Compound of Formula (V): W is absent. Rw j s H. R is -CH9CH(O). RP is H. U is OH The compound from Example 57 is treated with ozone under N2 followed by treatment with dimethylsulfide and triphenylphosphine. The intermediate is treated with ethanoUc HCl, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
  • Example 81 is OH
  • Example 80 The compound from Example 80 is treated with benzylamine in dry dichloromethane in the presence of molecular sieves (4A). The resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanoUc HCl, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on sihca gel to give the title compound.
  • Example 80 The compound from Example 80 is treated with O-phenylhydroxylamine-HCl in dry dichloromethane in the presence of triethylamine.
  • the intermediate is treated with ethanoUc HCl, and that product is refluxed with methanol overnight.
  • the crude product is purified by chromatography on sUica gel to give the title compound.

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US6437106B1 (en) * 1999-06-24 2002-08-20 Abbott Laboratories Process for preparing 6-o-substituted erythromycin derivatives
US20020115621A1 (en) 2000-08-07 2002-08-22 Wei-Gu Su Macrolide antibiotics
CN1197870C (zh) 2000-08-14 2005-04-20 大正制药株式会社 一种红霉素衍生物的制备方法及其中间体
TWI246515B (en) * 2001-05-30 2006-01-01 Abbott Lab An arylation method for the functionalization of O-allyl erythromycin derivatives
US6825172B2 (en) 2002-05-31 2004-11-30 Janssen Pharmaceutica, Nv 3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide antibacterial agents
ITMI20021726A1 (it) * 2002-08-01 2004-02-02 Zambon Spa Macrolidi ad attivita' antiinfiammatoria.
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CN105418706B (zh) * 2015-10-27 2019-05-17 华南理工大学 一种大环内酯类抗菌化合物及其制备方法与应用

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WO1986001513A1 (en) * 1984-08-23 1986-03-13 Beecham Group, P.L.C. Erythromycin derivatives
EP0487411A1 (de) * 1990-11-21 1992-05-27 Roussel Uclaf Erythromycinderivate, ihre Verfahren zur Herstellung, Zwischenprodukte und ihre Anwendung als Medikamente

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JP2000500133A (ja) * 1995-11-08 2000-01-11 アボツト・ラボラトリーズ 三環式エリスロマイシン誘導体
AU2340797A (en) * 1996-05-07 1997-11-26 Abbott Laboratories 6-o-substituted erythromycins and method for making them
WO1998018808A1 (fr) * 1996-10-31 1998-05-07 Taisho Pharmaceutical Co., Ltd. Derives de l'erythromycine
JP2000198795A (ja) * 1996-10-31 2000-07-18 Taisho Pharmaceut Co Ltd エリスロマイシンａ誘導体

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WO1986001513A1 (en) * 1984-08-23 1986-03-13 Beecham Group, P.L.C. Erythromycin derivatives
EP0487411A1 (de) * 1990-11-21 1992-05-27 Roussel Uclaf Erythromycinderivate, ihre Verfahren zur Herstellung, Zwischenprodukte und ihre Anwendung als Medikamente

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