Azalides are structurally similar to erythromycin A, except for the presence of a ring nitrogen atom at the 9a-position. The compounds of the invention are further distinguished from erythromycins and erythromycin-like compounds in that the cladinose moiety has been cleaved from the molecule, and a carbonyl group is present at position 3.

The 9a-azalides of the present invention are potent antibiotics which are useful for the treatment of gram positive and gram negative organisms. As such the compounds find utility in human and veterinary medicine for the treatment of infections caused by susceptible organisms.

SUMMARY OF THE INVENTION The present invention addresses a compound represented by formula I: or a salt or hydrate thereof wherein: R 1 1 and R12 are taken separately or together;

when taken separately, Rll is selected from the group consisting of: NR'R", O(CH2)nAr and S(CH2)nAr; and R ² represents a member selected from the group consisting of: H, C1-6 alkyl, uninterrupted or interrupted by 1-3 of 0, S(O)y, N, NH, NCH3 or C(O), and unsubstituted or substituted with 1-3 Ra groups, and (CH2)nAr wherein (CH2)n is alkylene, in which n is an integer of from 1 to 10, uninterrupted or interrupted by 1-3 of O, S(O)y wherein y is 0, 1 or 2, NH, NCH3 or C(O), and unsubstituted or substituted with 1-3 Ra groups; and Ar represents a 5-10 membered monocyclic or bicyclic aromatic ring system containing from 0-3 heteroatoms, which are selected from 0, S(O)y and N, unsubstituted or substituted with from 1- 3 groups Ra which are selected from halo, OH, OMe, NO2, NH2, CN, SO2NH2, C13 alkyl, and when two Ra groups are present, said two substituents may be taken in combination with any intervening atoms to represent a 5-6 membered ring, aromatic or non-aromatic, optionally containing 1-3 of O, S(O)y , N, NH, NCH3 or C(O); when taken together, R11 and R12 taken with the intervening atoms form an additional ring as shown in the following structure: wherein R' and Z are as defined below; Rn represents H, C1-6 alkyl, C1-6 alkyl interrupted by 1-3 of O, S(O)y, N, NH, NCH3 or C(O), unsubstituted or substituted with 1- 3 Ra groups, or (CH2)nAr wherein (CH2)n and Ar are as defined above, and R6 represents CH3,

or R6 and R11 are taken in conjunction with the intervening atoms and form an additional ring as shown in the following structure: Z represents CH2, C(O), C(NR"), P(O)OR", P(O)NRnR", Si(Rz)2, SO, S02, CH2CO, COCH2, COCH2CH2, CH2CH2CO, CH2CH2 or CH2XCH2; X represents CH2 , CHF, CF2, C=CH2, CHSR, CHCH3, C=S, C=O or CHOR; R represents H, CS2CH3, phenyl, C1-6 alkyl or C1-6 alkyl interrupted by 1-3 of O, S(O)y, N, NH, NCH3 or RZ represents C1-6 alkyl or phenyl; R' is selected from H, C1 3 alkyl, NHR"and (CH2)nAr, and R" represents H, C13 alkyl or (CH2)nAr.

Also included is a pharmaceutical composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.

Also included is a method of treating a bacterial infection in a mammalian patient in need of such treatment which is comprised of administering to said patient a compound of formula I in an amount which is effective for treating a bacterial infection.

DETAILED DESCRIPTION OF THE INVENTION The invention is described in connection with the following definitions unless otherwise specified.

Alkyl refers to C1-6 straight or branched chain alkyl groups. The alkyl group can be uninterrupted or interrupted of O, S(O)y wherein y is 0, 1 or 2, N, NH, NCH3 or C(O) as specified. When interrupted, a methylene spacer can be present which is adjacent to an interrupting moiety. Thus, this would include, for example, -CH2-O-

and -O-CH2-. When two or three of these interrupting groups is present, they may be separate or together. Me represents methyl.

Acyl refers to C1-5 alkyl-C(O)-.

When the group -(CH2)nAr is present, the alkyl portion - (CH2)n can be uninterrupted or interrupted as described above, with 0, S(O)y wherein y is 0, 1 or 2, NH, NCH3 or C(O). This includes groups where the interrupting atom is at either end of the chain. Thus, -C(O)- phenyl, -NH-phenyl, -C(O)NH-(CH2) 1- 10-phenyl, -CH2-O-phenyl as well as like groups are included. Additionally, the alkylene portion can be substituted with 1-3 groups selected from R .

Each Ra is independently selected from halo, OH, OMe, NO2, NH2, CN, SO2NH2, C 1-3 alkyl, and when two Ra groups are present, said two substituents may be taken in combination with any intervening atoms to represent a 5-6 membered ring, aromatic or non- aromatic, optionally containing 1-3 of O, S(O)y , N, NH, NCH3 or C(O).

Ar represents a monocyclic or bicyclic aromatic ring system containing from 0-3 heteroatoms, which are selected from 0, S and N, unsubstituted or substituted with from 1-3 groups selected from Ra which is halo, OH, OMe, NO2, NH2, CN, SO2NH2, C1-3 alkyl, and when two R substituent groups are attached to Ar, said substituents may be taken in combination with any intervening atoms to represent a 5-6 membered aromatic or non-aromatic ring, uninterrupted or interrupted by 1-3 of O, S(O)y, NH, NCH3 or C(O) wherein y is as previously defined. Examples of Ar and Ar substituted with 1-3 Ra groups include phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridyl, imidazolyl, pyrrolyl, thiophenyl, benzothiazolyl, thiazolyl, furanyl, benzofuranyl, indolyl, fluorenonyl, dibenzofuranyl and naphthosultamyl.

Halo means C1, F, Br or I.

A preferred aspect of the invention relates to compounds wherein Rn represents H, C 1-6 alkyl, C 1-6 alkyl substituted with 1-3 Ra groups or (CH2)nAr. Within this subset of compounds all other variables are as originally defined.

Another preferred aspect of the invention relates to compounds wherein R6 represents CH3.

Another preferred aspect of the invention relates to compounds wherein R6 and Rn taken together with the intervening atoms form a ring as shown in the following structure: in which Z represents CH2, C(O), C(NR"), P(O)OR", P(O)NRnR", Si(Rz)2, SO, S02, CH2CO, COCH2, COCH2CH2, CH2CH2CO or CH2XCH2 wherein R', R" and X are as originally defined. Within this subset of compounds, all other variables are as originally defined.

Another preferred aspect of the invention relates to compounds wherein Ar represents a monocyclic or bicyclic aromatic ring system containing from 0-2 heteroatoms, which are selected from O, S and N, unsubstituted or substituted with from 1-3 R groups which are selected from halo, OH, OMe, NO2, NH2, CN, SO2NH2 and C1-3 alkyl. Within this subset of compounds, all other variables are as originally defined.

Another preferred aspect of the invention relates to compounds wherein (CH2)nAr is present, and the alkylene chain is uninterrupted, and n is an integer of from 1-3. The alkylene group is either unsubstituted or substituted with from 1-3 Ra groups which are selected from halo, OH, OMe, NO2, NH2, CN, SO2NH2 and C1-3 alkyl. Within this subset, all other variables are as originally defined.

Another preferred aspect of the invention relates to compounds wherein R11 and R12 are taken separately, and R11 is selected from the group consisting of: OH and O(CH2)nAr, in which (CH2)n and Ar are as previously defined. Within this subset of compounds, all other variables are as originally defined.

Another preferred aspect of the invention relates to compounds wherein R11 and R12 are taken separately, and R12 represents H, C1-6 alkyl or (CH2)n-Ar. Within this subset of compounds, all other variables are as originally defined.

Another preferred aspect of the invention relates to compounds wherein R11 and R12 are taken together with the intervening atoms and form an additional ring as shown in the following structure: wherein Z represents CH2, C(O), C(NR"), P(O)OR", P(O)NRnR", Si(Rz)2, SO, SO2, CH2CO, COCH2, COCH2CH2, CH2CH2CO or CH2XCH2 wherein R', R" and X are as originally defined. Within this subset of compounds, all other variables are as originally defined.

A preferred subset of compounds of the present relates to compounds wherein: Rn represents H, C 1-6 alkyl, C 1-6 alkyl substituted with 1- 3 Ra groups or (CH2)nAr; R6 represents H or CH3; or R6 and Rn are taken together with the intervening atoms to form a ring as shown in the following structure: in which Z represents CH2, C(O), C(NR"), P(O)OR", P(O)NRnR", Si(RZ)2, SO, SO2, CH2CO, COCH2, COCH2CH2, CH2CH2CO, CH2CH2 or CH2XCH2 wherein R', R" and X are as originally defined;

Ar represents a monocyclic or bicyclic aromatic ring system containing from 0-2 heteroatoms, which are selected from 0, S and N, unsubstituted or substituted with from 1-3 R groups which are selected from halo, OH, OMe, NO2, NH2, CN, SO2NH2 and C13 alkyl; (CH2)n represents an alkylene chain which is uninterrupted, and n is an integer of from 1-3, unsubstituted or substituted with from 1-3 Ra groups which are selected from halo, OH, OMe, NO2, NH2, CN, SO2NH2 and C13 alkyl; R11 and R12 are taken separately, and R11 is selected from the group consisting of: OH and O(CH2)nAr, in which (CH2)n and Ar are as previously defined, and R12 represents H, C1-6 alkyl or (CH2)n-Ar, or R11 and R12 are taken together with the intervening atoms and form an additional ring as shown in the following structure: wherein Z is as originally defined.

Specific compounds which are included in the present invention are set forth below.

Table 1 # Rn R6 R' Ar 1 CH3 CH3 (CH2)4Ar ¼ 2 CH3 CH3 (CH2)4Ar 2 CH3 CH3 (CH2)4Ar 3 CH3 CH3 (CH2)5Ar 4 CH3 CH3 (CH2)3Ar o8-N 5 CH3 CH3 (CH2)4Ar 6 CH3 CH3 (CH2)4Ar 7 ---CH2--- (CH2)4Ar 8 ---CH2--- NH(CH2)3Ar 9 CH3 CH3 NH(CH2)3Ar Table 2 Rn R" R6 R11 R12 Ar 10 CH3 CH3 O(CH2)3Ar H ¼ 11 CH3 CH3 OH (CH2)3Ar iD¼if N 12 CH3 CH3 O(CH2)3Ar H ¼))) 13 CH3 CH3 O(CH2)4Ar H 14 CH3 CH3 S(CH2)4Ar H [¼i¼)¼ 15 (CH2)4Ar CH3 OH H 16 (CH2)4SO2Ar CH3 OH H 17 CH3 CH3 OH H 18 -P(O)OCH3- OH H 19 -P(O)OCH3- OH H 20 -COCH2- OH H 21 -COCH2- OH H Table 3 ~ Z Rn R6 Ar N 22 C=N(CH2)3Ar CH3 CH3 < W 1 23 | P(O)O(CH2)3ArA CH3 | CH3 MW 24 P(O)NH(CH2)3Ar CR3 CR3 . l l

Numbering of the 9a-aza-3-ketolides described herein is in accordance with the following scheme.

The compounds of the present invention are prepared from 9a-aza-9-deoxo-9a-homo-erythromycin A by a variety of synthetic routes. The process is illustrated by the following generic scheme: Scheme A

With reference to Scheme A, X, R6, Rn, R11, and R12 are as defined with respect to the compounds of formula I.

Since 9a-aza-9-deoxo-9a-homo-erythromycin A is prepared from erythromycin, the compounds of the present invention are ultimately derived from erythromycin as shown in Scheme B. It will be further recognized that the the compounds of the present invention can be prepared from erythromycin without proceeding through the azalide intermediate shown above by simply altering the order of the steps described herein for the conversion of that intermediate to the compounds of the present invention and the steps required to introduce the 9a nitrogen.

Scheme B 0 NMe2 HO4 NMe2 N 3' a HO,, several steps R12O R60" HO HO OMe tr*u At some point during the synthetic sequence, it is necessary to remove the cladinose attached at C-3 of the starting azalide.

Depending on the exact nature of the final synthetic target, the cladinose removal may be best effected at either an early or late stage of the synthesis. This is generally accomplished by treating the macrolide with acid in either aqueous or alcoholic solution. Thus, a solution of the macrolide in an alcohol such as methanol, ethanol, or the like containing from 0.5 to 5% of a strong acid such as hydrochloric acid, sulfuric acid, or the like is stirred for 1 to 36 hours at a temperature ranging from 0°C to 300C. Alternatively, a solution of the macrolide in a 0. 1N to 1 N aqueous solution of a strong acid such as hydrochloric acid, sulfuric acid, or the like is stirred for 1 to 36 hours at a temperature ranging from about 0°C to 300C. The reaction is worked up and the product macrolide isolated by first making the reaction mixture basic by adding

an aqueous solution of a base such as sodium hydroxide, sodium bicarbonate, potassium carbonate and the like then extracting the macrolide product with a suitable organic solvent such as chloroform, ethyl acetate, and the like. If the reaction is run in an alcoholic solvent, the extraction procedure may be improved by first concentrating the reaction mixture under vacuum, preferably after addition of aqueous base to neutralize the acid. When working in the erythromycin series (ketone at C-9, free OH group at C-6), the C-9 ketone must be protected (e.g. as an oxime) before attempting to remove the cladinose under the acidic conditions described above. In the azalide series (C-9 ketone removed with the addition of the 9a-nitrogen), no protection of a ketone at C-9 is necessary.

During alkylation of the C-3, 6, 11, or 12 hydroxyl group, it is necessary to protect the nitrogen at C-3' in order to prevent quaternization of the nitrogen. This can be accomplished by protection of the desosamine as the 2',3'-bis-CBZ derivative by using standard macrolide chemistry techniques. Alternatively, the 3'-nitrogen atom can be protected as an arylsulfonamide by N-demethylation followed by sulfonylation with an appropriate sulfonyl halide or sulfonic anhydride.

It is not generally necessary to protect the 9a-nitrogen during alkylation reactions. However, protection of the 9a-nitrogen may be useful since it can alter the order of reactivity of the various hydroxyl groups to alkylation.

Some reactions, including but not limited to alkylation reactions, may also necessitate protection of other hydroxyl groups.

This may be accomplished by protection as a silyl ether, an ester, a mixed carbonate, or any of a variety of hydroxyl protecting groups well-known to those skilled in the art.

Alkylation of the C-3, 6, 11, or 12 hydroxyl group may be accomplished by treating a solution of a suitably protected macrolide in a suitable solvent such as dimethylformamide, tetrahydrofuran, and the like with a strong base such as sodium hydride, potassium hexamethyldisilazide, and the like at a temperature ranging from -40°C to 250C for 1 to 30 minutes then adding a suitable alkylating reagent such as an alkyl iodide, an alkyl bromide, an alkyl

trifluoromethanesulfonate, and epoxide, and the like and stirring the resulting reaction mixture at a temperature ranging from -40°C to 450C for 15 minutes to 4 hours (appropriate temperature and length of time depends on the exact nature of the alkylating reagent).

Many of the compounds of the present invention contain fewer oxygen atoms attached to the macrolide ring than are present in erythromycin. Such deoxy analogs can be prepared by employing one of many deoxygenation methods for reductive removal of a hydroxyl group. For example, the hydroxyl group can be converted to a xanthate ester by reaction with a base such as sodium hydride, potassium hexamethyldisilazide, and the like in a solution of a suitable solvent such as tetrahydrofuran, ether, dioxane and the like at temperatures ranging from -20°C to 300C for 1 to 30 minutes followed by reaction of the resulting alkoxide with excess carbon disulfide and iodomethane to form a methyl xanthate. The methyl xanthate can be purified using standard techniques or, alternatively, may be subjected to the radical deoxygenation procedure without purification. A solution of the methyl xanthate in a suitable solvent such as toluene, benzene, and the like is treated with a radical initiator such as azobis-isobutyrylnitrile (AIBN), triethylborane, and the like and an excess of a hydride source such as tributyltin hydride, triphenyltin hydride, and the like at a temperature ranging from room temperature to 1250C for 1 to 24 hours. The reaction is worked up and the product macrolide isolated using standard macrolide chemistry techniques.

In compounds containing a cyclic carbamate moiety at C- 11 and C-12 of the macrolide ring, the cyclic carbamate may be introduced into the erythromycin molecule before the ring expansion and incorporation of the 9a-nitrogen using standard techniques of macrolide chemistry which have been published in the literature and are well known to those skilled in the art. Once the cyclic carbamate moiety is in place, the 9a-nitrogen may be installed using the standard ring expansion techniques which have been previously published. For compounds containing an alkyl group appended to the nitrogen of the 11,12-cyclic carbamate, the alkyl group may either be incorporated during the

construction of the cyclic carbamate or may be added to the completed cyclic carbamate via an alkylation procedure.

Alternatively, the 11,12-cyclic carbamate can be introduced at a stage in the sequence with the 9a nitrogen.

Introduction of the 3-keto group is accomplished by oxidation of a suitably protected precursor with a hydroxyl group at C- 3 using one of the many methods for oxidation of secondary alcohols which are well-known to those skilled in the art. For example, a solution of the 3-hydroxy precursor compound in a suitable solvent such as dichloromethane, chloroform, dichloroethane and the like is treated with from 0.95 to 2 molar equivalents of an oxidation reagent such as pyridinium chlorochromate, pyridinium dichromate, Dess-Martin periodinane, chromic acid and the like for 0.1 to 24 hours at a temperature ranging from -40°C to 400C. The reaction is worked up and the product macrolide isolated by simply filtering the reaction mixture through a piece of filter paper or through a plug of silica gel and evaporating the filtrate under vacuum. Alternatively, the reaction may be worked up by adding an aqueous solution of a base such as sodium hydroxide, sodium bicarbonate, potassium carbonate and the like then extracting the macrolide product with a suitable organic solvent such as chloroform, ethyl acetate, and the like. Evaporation of the organic extract under vacuum then affords the product. Alternatively, oxidation procedures commonly referred to by those skilled in the art as Moffat or Swern oxidations, which involve the use of activated DMSO reagents, may be employed for the oxidation of a 3-hyroxyl group to a 3-ketone. Oxidation using the Dess-Martin periodinane is preferred.

The synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are well known to those skilled in the art. The deprotected final product is then purified, as necessary, using standard techniques such as silica gel chromatography, HPLC on silica gel or on reverse phase silica gel, and the like or by recrystallization.

The final product may be characterized structurally by standard techniques such as NMR, IR, MS and UV. For ease of

handling, the final product, if not crystalline, may be lyophilized from, e.g., benzene, tert-butanol and the like, to afford an amorphous, easily handled solid.

The compounds are useful in various pharmaceutically acceptable salt forms. The term "pharmaceutically acceptable salt" refers to those salt forms which would be apparent to the pharma- ceutical chemist. i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.

Pharmaceutically acceptable salts include conventional non-toxic salts or quarternary ammonium salts formed, e.g., from non-toxic inorganic or organic acids. Non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methane- sulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods.

Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid or base, in a suitable solvent or solvent combination.

The compounds of this invention may be used in a variety of pharmaceutical preparations. They may be employed in powder or crystalline form, in liquid solution, or in suspension.

They may be administered by a variety of means; those of principal interest include: topically, orally and parenterally by injection.

Oral compositions may take such forms as tablets, capsules, oral suspensions and oral solutions. The oral compositions may utilize conventional formulating agents, and may include sustained release properties as well as rapid delivery forms. The preferred pharmaceutical composition is a table, capsule, suspension or solution, which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.

The dosage to be administered depends to a large extent upon the condition and size of the subject being treated, the route and frequency of administration, the sensitivity of the pathogen to the particular compound selected, the virulence of the infection and other factors. Such matters are left to the routine discretion of the physician according to principles of treatment well known in the antibacterial arts.

The compositions for human delivery per unit dosage, whether liquid or solid, may contain from about 0.01% to as high as about 99% of active material, the preferred range being from about 10-60%. The composition will generally contain from about 15 mg to about 2.5 g of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 25 mg to 1000 mg.

The preferred method of administration is oral.

For adults, about 5-50 mg of the compound per kg of body weight given one to four times daily is preferred. The preferred dosage is 250 mg to 1000 mg of the compound given one to four times per day. More specifically, for mild infections a dose of about 250 mg two or three times daily is recommended.

For severe infections caused by organisms at the upper limits of sensitivity to the antibiotic, a dose of about 1000-2000 mg three to four times daily may be recommended.

For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg may be recommended.

EXAMPLE 1 9-Deoxo-9a-aza-3-descladinosyl-9a-homoerythromycin A 11,12- carbonate-9a-N 6-O-carbamate NMe2 NMe2 " > AcO,,, HO,, o'.OO Ac2O HO .O NaH HO Js pyridine HOi OMe DMAP ~ > S OMe THF O¼M{HWMAY to O½{:Ac ° o. O NMe2 NMe2 H 0, oO ,,N O 0 phosgene 0 0.1 M O toluene OMe | OMe "" AcOH l DIPEA I DlPEA O 0.OAc K OAc NMe2 NMe2 4 Jg)h( 0 OO °>>°t 1N HCI °= 0 OMe CtoH 0 0

Step 1: 2'*4"-bis(O-Acetyl)-9-deoxo-9a-aza-9a-N*6-O-methYlene-9a- homoervthromvcin A A solution of 9-deoxo-9a-aza-9a,6-O-methylene-9a- homoerythromycin A (3.07 g, 4.1 mmol), 4-dimethylaminopyridine (125 mg, 1.02 mmol), and pyridine (3.5 mL, 43.3 mmol) in 5:1 ether:tetrahydrofuran (135 mL) is cooled to OOC with stirring. Acetic anhydride (3.9 mL, 41.3 inmol) is added dropwise. The cooling bath is thereafter removed and the reaction allowed to stir at room temperature. The reaction is partitioned between ethyl acetate and saturated aqueous potassium carbonate. The organic layer is washed with brine, dried (anhydrous sodium sulfate), filtered, and evaporated to give the title compound.

Step 2: 2's4"-bis(O-Acetyl!-9-deoxo-9a-aza-9a*6-O-methYlene-9a- homoervthromycin A 11 12-carbonate A solution of 2',4" -bis(O-acetyl)-9-deoxo-9a-aza-9a,6-O- methylene-9a-homoerythromycin A (1.0 g, 1.2 mmol) in anhydrous tetrahydrofuran (7 mL) is stirred at room temperature as sodium hydride (104 mg of 60% dispersion in mineral oil, 2.6 mmol) is added.

l,1'-Carbonyldiimidazole (0.88 g, 5.4 mmol) is then added with further stirring at 700C. Saturated aqueous sodium bicarbonate is added dropwise. The aqueous layer is extracted twice with ethyl acetate. The combined organic layers are washed with 5% aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the title compound.

Step 3: 2' 4"-bis(O-Acetvl)-9-deoxo-9a-aza-9a-homoerythromycin A 11*12-carbonate A solution of 0.1 M aqueous acetic acid (250 mL) is added to 2' ,4"-bis(O-acetyl)-9-deoxo-9a-aza-9a,6-O-methylene-9a- homoerythromycin A 11,12-carbonate (1.09 g, 1.2 mmol). The resulting suspension is stirred at room temperature for 8 hours. The aqueous layer is washed with ethyl acetate (5 mL). The aqueous layer is made basic by the dropwise addition of saturated aqueous potassium carbonate and extracted with ethyl acetate (2 x 250 mL). The combined organic layers are washed with brine, dried over anhydrous potassium carbonate, and evaporated to give the title compound.

11' 1 2-carbonate-9a-N,-6-O-carbamate A solution of 2',4"-bis(O-acetyl)-9-deoxo-9a-aza-9a- homoerythromycin A 11,12-carbonate (0.86 g, 1.02 mmol) and 4- dimethylaminopyridine (32.4 mg, 0.27 mmol) in dichloromethane (8 mL) is stirred under a nitrogen atmosphere. N,N- Diisopropylethylamine (8.0 mL, 45.9 mmol) is added followed by the dropwise addition of phosgene (20% in toluene, 8.0 mL, 20.3 mmol).

The reaction is stirred at room temperature, and partitioned between dichloromethane and saturated aqueous potassium carbonate. The organic layer is washed with water, dried (anhydrous potassium carbonate), filtered, and evaporated to give the title compound.

Step 5: 2'-O-Acetyl-3-descladinosyl-9-deoxo-9a-aza-9a- homoerythromycin A 11.12-carbonate-9a-N.-6-O-carbamate A solution of 2',4"-bis(O-acetyl)-9-deoxo-9a-aza-9a- homoerythromycin A 11,1 2-carbonate-9a-N,6-O-carbamate( 1.29 g) in 0.86M aqueous hydrochloric acid (350 mL) is stirred at room temperature to completion. The solution is made basic with saturated aqueous potassium carbonate and extracted with ethyl acetate (3 x 300 mL). The combined organic layers are washed with brine, dried (anhydrous sodium sulfate), filtered, and evaporated to produce the crude product.

The crude solid is dissolved in 2:1 hexane:acetone and loaded onto a silica gel column (2.75 cm dia., 22 g of silica, 20 mL fractions), eluted with the same solvent system. The appropriate fractions can be combined, evaporated, and lyophilized (from benzene) to give the title compound.

Step 6: 3-descladinosyl-9-deoxo-9a-aza-9a-homoerythromycin A 11.12- carbonate-9a-N,-6-O-carbamate A solution of 2'-O-acetyl-9-deoxo-9a-aza-9a,6-O-carbonyl- 11-0,1 2-O-carbonyl-3-descladinosyl-9a-homoerythromycin A (11.1 mg, 0.017 mmol) is stirred in methanol (3 mL). The solvent is evaporated and the residue lyophilized (from benzene) to give the title compound.

EXAMPLE 2 3-descladinosyl-3-oxo-9-Deoxo-9a-aza-9a-homoerythromvcin A 11.12- carbonate-9a-N,-6-O-carbamate

Step 1: 2'-O-Acetyl-3-descladinosvl-3-oxo-9-deoxo-9a-aza-9a- homoerythromycin A 11.12-carbonate-9a-N.-6-O-carbamate A solution of Dess-Martin periodinane (200.1 mg, 0.47 mmol) and 2'-O-acetyl-3-descladinosyl-9-deoxo-9a-aza-9a- homoerythromycin A 11,12-carbonate-9a-N,-6-O-carbamate (50.8 mg, .076 mmol) in dichloromethane (3 mL) is stirred at reflux for 90 minutes. The reaction mixture is partitioned between dichloromethane and saturated aqueous potassium carbonate, the layers separated, and the organic layer washed with water (10 mL), dried (anhydrous potassium carbonate), filtered, and evaporated. The residue is dissolved in 1:1 dichloromethane:ether (20 mL). A solution containing sodium bicarbonate (1.3 g) and sodium thiosulfate (4.6 g) in water (15 mL) is added. Saturated sodium bicarbonate is added and the layers are separated. The combined organic layers are dried over anhydrous sodium sulfate, filtered and evaporated. The product is combined with 2:1 hexane:acetone, loaded onto a 2 x 14.5 cm silica gel column and was eluted with 2:1 hexane:acetone. The appropriate fractions are combined and evaporated to give the title compound.

Step 2: 3-descladinosvl-3-oxo-9-deoxo-9a-aza-9a-homoervthromvCin A 11.1 2-carbonate-9a-N.-6-O-carbamate A solution of 2'-O-acetyl-3-descladinosyl-3-oxo-9-deoxo- 9a-aza-9a-homoerythromycin A 11,12-carbonate-9a-N,-6-O-carbamate in methanol (5 mL) is stirred at room temperature. The solvent is evaporated and the residual solid lyophilized from benzene to give the title compound.

EXAMPLE 3 3-descladinosvl-3-oxo-9-deoxo-9a-aza-9a-N 6-O-methylene-9a- homoervthromvcin A 11.12-carbonate

Step 1: 2' -O-acetvl-9a-N.6-O--methylene-9-deoxo-9a-aza-9a- homoerythromycin A To a solution of 2.98 g of 9-deoxo-9a-aza-9a- homoerythromycin A in 70 mL of chloroform is added 0.750 mL of 37% aq. formaldehyde. The mixture is refluxed for 1.5 hours, after which time the reaction is diluted with 150 mL chloroform and extracted with 50 mL of sat. aq. potassium carbonate. The organic layer is separated, dried over anhydrous potassium carbonate, and the solvent removed under reduced pressure. The crude residue is dissolved in 20 mL of 1:1 ethyl acetate:methylene chloride. 0.800 mL of acetic anhydride is added, and the mixture is stirred at room temperature for 1.5 hours. The solvent is removed under reduced pressure to afford the title compound.

Step 2: 2' -O-acetyl-9a-N.6-O--methvlene-9-deoxo-9a-aza-9a- homoervthromycin A-4"-imidazoylcarbamate- 11 12 carbonate To a solution of 0.103 g (0.127 mmol) of 2'-O-acetyl-aa- N,6-O-methylene-9-deoxo-9a-aza-9a-homoerythromycin A in 1.0 mL of tetrahydrofuran is added 0.103 g of carbonyldiimidazole (5 eq.), then 12.7 mg of sodium hydride (60% oil dispersion). The mixture is refluxed for 25 minutes. The reaction is diluted with 50 mL ethyl acetate and washed three times with 10 mL of sat. aq. sodium bicarbonate. The organic layer is separated, dried over anhydrous potassium carbonate, and the solvent is removed under reduced pressure to afford the title compound.

Step 3: 2' -O-acetvl-3-descladinosyl-9-deoxo-9a-aza-9a- homoerythromycin A- 11 12 carbonate A solution of 0.110 g (0.127 mmol) of 2'-O-acetyl-9a-N,6- O-methylene-9-deoxo-9a-aza-9a-homoerythromycin A-4"- imidazoylcarbamate-1 1,12 carbonate in 5.0 mL of 0.25 N aq. HCl is allowed to stir at room temperature for 12 hours. The reaction is diluted with 50 mL ethyl acetate and washed three times with 30 mL of sat. aq. sodium bicarbonate. The organic layer is separated, dried over anhydrous potassium carbonate, and the solvent is removed under reduced pressure to afford the title compound.

Step 4: 2' -O-acetyl-3-descladinosyl-9a-N6-O-methvlene-9-deoxo-9a- aza-9a-homoerythromycin A-11.12 carbonate To a solution of 0.074 g (0.122 mmol) of 2'-O-acetyl-3- descladinosyl-9-deoxo-9a-aza-9a-homoerythromycin A- 11,12 carbonate in 2.0 mL of chloroform is added 0.050 mL of 37% aq. formaldehyde.

The mixture is refluxed for 1 hour, after which time the reaction is diluted with 150 mL chloroform and extracted with 50 my of sat. aq.

potassium carbonate. The organic layer is separated, dried over anhydrous potassium carbonate, and the solvent is removed under reduced pressure to afford the title compound.

Step 5: 2' -acetoxy-3-descladinosvl-3-oxo-9a-N*6-O-methYlene-9-deoXo- 9a-aza-9a-homoervthromycin A- 11 12 carbonate To a solution of 0.158 g of 2'-O-acetyl-3-descladinosyl-9a- N,6-O-methylene-9-deoxo-9a-aza-9a-homoerythromycin A- 11,12 carbonate in 1.6 mL of chloroform is added 158 mg of the Dess-Martin periodinane reagent. The mixture is stirred at room temperature for 35 minutes, after which time the reaction is diluted with 30 mL chloroform and 30 mL of saturated aqueous sodium bicarbonate. The organic layer is separated and the aqueous layer is back extracted with 15 mL of methylene chloride. The combined organics are dried over anhydrous potassium carbonate, and the solvent is removed under reduced pressure. The crude material is chromatographed on silica gel eluted

with 1:1 hexane:acetone. The fractions containing the desired product are combined and evaporated to afford the title compound.

Step 6: 3-descladinosyl-3-oxo-9a-N 6-O-methylene-9-deoxo-9a-aza-9a- homoerythromycin A-1112 carbonate A solution of 0.035 g of 2'-O-acetyl-3-descladinosyl-3-oxo- 9a-N,6-O-methylene-9-deoxo-9a-aza-9a-homoerythromycin A- 11,12 carbonate in 2.0 mL of methanol is stirred at room temperature for 5.5 hours, after which time the solvent is removed under reduced pressure.

The crude material is chromatographed on silica gel eluting with 1:4 hexane:acetone. The fractions containing the desired product are combined and evaporated to afford the title compound.