The 8a-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: X represents CH2, CHF, CF2, C=CH2, CHSR, CHCH3, C=S, C=O or CHOR;

R represents H, C1-6 alkyl, CS2CH3 or phenyl, said C1-6 alkyl being uninterrupted or interrupted by O, S(O)y wherein y is 0, 1 or 2, NH or C(O), and being unsubstituted or substituted with 1-3 R groups, as defined below; Rn represents H, C1-6 alkyl or -(CH2)nAr wherein n represents an integer of from 1 to 10, said Cl-6 alkyl chain and -(CH2)n being uninterrupted or interrupted by 1-3 of O, S(O)y, NH, NCH3 or C(O) wherein y is as previously defined, and being unsubstituted or substituted with 1-3 Ra groups as defined below, or Rn is taken in conjunction with R6 as defined below; Ar represents a 5-10 membered 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 Ra which are selected from halo, OH, OMe, N02, NH2, CN, S02NH2, C1-3 alkyl, and when two substituent groups are attached to Ar, said two substituents may be taken in combination with any intervening atoms to represent a 5-6 membered ring, aromatic or non-aromatic, containing from 0-2 heteroatoms as defined above; R11 is selected from the group consisting of: OH, NR'R", O(CH2)nAr and S(CH2)nAr, wherein (CH2)n and Ar are as previously defined; R12 is selected from the group consisting of: H, C1-6 alkyl and (CH2)nAr wherein (CH2)n and Ar are as previously defined; or R11 and R12 taken together with the intervening atoms form an additional ring of the following structure: wherein R' is selected from H, C13 alkyl, NHR"and (CH2)nAr wherein (CH2)n and Ar are as previously defined;

R" represents H, C13 alkyl or (CH2)nAr wherein (CH2)n and Ar are as defined above; 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 wherein R" and X are as defined above; RZ represents C1-6 alkyl or phenyl; R6 represents H or CH3; and Rn is as defined above; or R6 and Rn taken together with the intervening atoms form the following structure: in which Z is as described above.

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 as used herein refers to C16 straight or branched chain alkyl groups which are uninterrupted or interrupted by 1-3 of N, O, S(O)y wherein y is 0, 1 or 2, or C=O as specified, and which are unsubstituted or substituted with from 1-3 R groups. 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 moieties are present, they may be separate or together.- Me represents methyl.

Each Ra is selected from halo, OH, OMe, NO2, NH2, CN, S02NH2, Cl-3 alkyl, and when two substituent 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, containing from 0-2 heteroatoms as defined above.

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

When the group -(CH2)nAr is present, the alkyl portion -(CH2)n is uninterrupted or interrupted as described above, with 1-3 of O, S(O)y wherein y is 0, 1 or 2, NH, NCH3 or C(O), and is unsubstituted or substituted with 1-3 Ra groups. 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 lo-phenyl, -CH2-O-phenyl as well as like groups are included. More than one interrupting moiety can be present, separate or together. Thus, -OC(O)-, S(O)yNH -C(O)NH- and similar groups are included, as well as polyethers, polythioethers and the like.

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 two substituents may be taken in combination with any intervening atoms to represent a 5-6 membered aromatic or non-aromatic ring. Examples include phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridyl, imidazolyl, pyrrolyl, thiophenyl, benzothiazolyl, thiazolyl, furanyl, benzofuranyl, naphthosultamyl, dibenzofuranyl, fluorenonyl, phenanthrenyl and indolyl.

Halo means C1, F, Br or I.

A preferred aspect of the invention relates to compounds of formula I wherein X contained in the azalide ring represents CH2, CHF, CF2. Within this subset of compounds, all other variables are as originally defined.

Another preferred aspect of the invention relates to compounds of formula I wherein X contained in the azalide ring represents C=CH2, C-S or CHSR. Within this subset of compounds, all other variables are as originally defined.

Yet another preferred aspect of the invention relates to compounds of formula I wherein X contained in the azalide ring represents C(O) or CHOR. Within this subset of compounds, all other variables are as originally defined.

Another preferred aspect of the invention relates to compounds wherein Rn represents H, C 1-6 alkyl 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 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 Ra groups which are selected from halo, OH, OMe, N02, NH2, CN, S02NH2 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 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 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 of 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, CH2CH2 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 R6 and Rn taken together with the intervening atoms form the following structure: in which Z is as described above. Within this subset all other variables are as originally defined.

A preferred aspect of the invention relates to compounds of formula I wherein: X contained in the azalide ring represents CH2, CHF or CF2; Rn represents H, C 1-6 alkyl or (CH2)nAr, wherein 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 Ra groups selected from halo, OH, OMe, N02, NH2, CN, S02NH2 and C1-3 alkyl, or Rn is taken in conjunction with R6 as defined below; R11 is selected from the group consisting of: OH and O(CH2)nAr, in which (CH2)n and Ar are as previously defined; 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 of the following structure: wherein 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; R6 is H or CH3, or R6 and Rn taken together with the intervening atoms form the following structure: in which Z is as described above.

Another preferred aspect of the invention relates to compounds of formula I wherein: X contained in the azalide ring represents C=CH2, C=S or CHSR; Rn represents H, C1-6 alkyl or (CH2)nAr, wherein 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 Ra groups selected from halo, OH, OMe, N02, NH2, CN, S02NH2 and C1-3 alkyl, or Rn is taken in conjunction with R6 as defined below; R11 is selected from the group consisting of: OH and O(CH2)nAr, in which (CH2)n and Ar are as previously defined; 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 of the following structure: wherein 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 wherein R', R" and X are as originally defined; R6 is H or CH3, or R6 and Rn taken together with the intervening atoms form the following structure: in which Z is as described above.

Another preferred aspect of the invention relates to compounds of formula I wherein: X contained in the azalide ring represents C(O) or CHOR; Rn represents H, C1-6 alkyl or (CH2)nAr, wherein 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 Ra groups selected from halo, OH, OMe, N02, NH2, CN, S02NH2 and C1-3 6 alkyl, or Rn is taken in conjunction with R6 as defined below; R11 is selected from the group consisting of: OH and O(CH2)nAr, in which (CH2)n and Ar are as previously defined; 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 of 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, CH2CH2 or CH2XCH2 wherein R', R" and X are as originally defined; R6 is H or CH3, or R6 and Rn taken together with the intervening atoms form the following structure: in which Z is as described above.

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

Table 1 # X Rn R6 R' Ar 1 CH2 CH3 H (CH2)4Ar (¼ 2 CH2 CH3 H (CH2)4Ar 3 CH2 CH3 H (CH2)4Ar 4 CH2 CH3 H (CH2)3Ar o£Sii 6 CF2 CH3 CH3 (CH2)4Ar < 7 CH2 ---CH2--- (CH2)4Ar 9 CH2 CH3 H NH(CH2)3Ar 8 CH2 CH2--- z NH(CH2)3Ar X I 9 ICH2WCH3 z H Z NH(CH2)3Ar / Table 2 ~ x Rn R6 R11 R12 Ar 10 J CH2 | CH3 H O(CH2)3Ar H 1%) MN 11 CH2 CH3 I OH (CH2)3Ar n 13 CHF CH3 CH3 O(CH2)4Ar H W ¼) 14 a CH2 | CH3 H I S(CH2)4Ar | H 15 CH2 (CH2)4Ar H OH H MN 16 CH2 (CH2)4S02Ar H OH H 17 C=O CH3 CH3 OH H 18 CH2 -P(O)OCH,- OH H ------ 19 C=O P(O)OCH3-- OH H 20 CH2 --C(O)CH2-- OH H 21 C=O --C(O)CH2-- OH H Table 3 # Z X n R6 Ar 22 C=N(CH2)3Ar CH2 CH3 H

23 P(O)O(CH2)3Ar CH2 CH3 H < 24 P(O)NH(CH2)3Ar CH2 CH3 H Numbering of the 8a-azalides described herein is in accordance with the following scheme.

The compounds of the present invention are prepared from 8a-aza-9-deoxo-8a-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, R1 1, and R12 are as defined with respect to the compounds of formula I.

Since 8a-aza-9-deoxo-8a-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 8a nitrogen.

Scheme B NMe2 Rn ~ NMe2 = H NMe2 \ HO,,, NMe2 HO" z to O R11" J X so oW HO,,, HO z several steps > ,,,""' HO Hd < OMe OMe x 8 0 O OH O 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 30"C. Alternatively, a solution of the macrolide in a O. 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, preferabl-y 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 8a-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 8a-nitrogen during alkylation reactions. However, protection of the 8a-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 -400C to 250C for 1 to 30 minutes then adding a suitable alkylating reagent such as an alkyl iodide, an alkyl bromide, an alkyl trifluoromethane- sulfonate, 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 hexa- methyldisilazide, 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 30"C for 1 to 30 minutes followed by reaction of the resulting alkoxide with excess carbon do sulfide and iodomethane to form a methyl xanthate. The methyl xanthate can be purified using standard techniques or, alternatively, may be subjected to the radical deoxygena- tion 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), triethyl- borane, 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 8a-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 8a-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 introducted at an intermediate stage in the sequence with the 8a- nitrogen.

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-8a-aza-8a-methvl-3-descladinosyl-8a-homoervthromycin A- 1 1.12-carbonate

Step 1: 9-Deoxo-8a-aza-8 a-methyl-3-descladinosyl-8 a- homoervthromycin A A solution of 9-deoxo- 8 a-aza- 8 a-methyl-8 a-homoerythro- mycin A (2.0 g, 2.67 mmol) in 0.25N aqueous hydrochloric acid (100 mL) was stirred at room temperature for 24 hours. The solution was washed with chloroform (2 x 60 mL). The pH of the combined aqueous layers was adjusted to approximately 10 by dropwise addition of SN aqueous sodium hydroxide. The cloudy aqueous layer was extracted with chloroform (3 x 60 mL). The combined organic extracts were dried over anhydrous potassium carbonate, filtered, and evaporated to give the title compound as a white solid (1.68 g) which was used without further purification.

Step 2: 2'-O-Acetyl-9-deoxo-8a-aza-8a-methyl-3 -descladinosyl-8a- homoerythromycin A A solution of 9-deoxo- 8a-aza-8a-methyl-3 -descladinosyl-8a- homoerythromycin A (2.67 mmol) in dichloromethane (30 mL) stirred under a nitrogen atmosphere as acetic anhydride (0.54 mL, 5.7 mmol) was added. After stirring for 3 hours at room temperature, the solvent was removed in vacuo. The residual white foam was dissolved in water (50 mL) and the pH was adjusted to between 10-11 with SN aqueous sodium hydroxide. The aqueous layer was extracted with dichloromethane (3 x 60 mL). The combined organic extracts were dried (anhydrous sodium sulfate), filtered, and evaporated to give the title compound (1.25 g, 73% for 2 steps).

Step 3: 2'-O-Acetyl-9-deoxo-8a-aza-8a-methyl-3-descladinosyl-8a- homoervthromvcin A 11 12-carbonate A solution of 2'-O-acetyl-9-deoxo-8a-aza-8a-methyl-3- descladinosyl-8a-homoerythromycin A (100 mg, 0.16 mmol) in anhydrous tetrahydrofuran (0.53 mL) was stirred at room temperature as sodium hydride (60% dispersion in mineral oil, 13.3 mg, 0.33 mmol) and l,1'-carbonyldiimidazole (120.4 mg, 0.74 mmol) were added. The resulting mixture was stirred at 55-60"C for 80 minutes. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous sodium sulfate), and evaporated to give a yellow solid (100 mg). The crude solid was purified on a silica gel column (12 g, 2.75 cm dia.) eluted with 1:1 hexane:acetone. The fractions containing product were combined and evaporated to give the title compound (51.4 mg, 49%).

Step 4: 9-Deoxo-8a-aza- 8a-methyl-3 -descladinosyl-8a- homoervthromycin A 11 12-carbonate A solution of 2'-O-acetyl-9-deoxo-8a-aza- 8 a-methyl-3- descladinosyl-8a-homoerythromycin A 11,12-carbonate (15 mg, 0.023 mmol) in methanol (10 mL) was stirred overnight at room temperature then concentrated under vacuum. The resulting oil was dissolved in benzene (3 mL) and lyophilized to give the title compound (10 mg) as a white solid.

EXAMPLE 2 3-O-Acetyl-9-deoxo-8a-aza-8a,6-O-methylene-3-descladinosyl-8 a- homoervthromycin A 11 12-carbonate Step 1: 2',3-bis-(O-Acetyl)-9-deoxo-8a-aza-8a,6-O-methylene-3- descladinosvl-8a-homoerythromvcin A 11 12-carbonate A solution of 2'-O-acetyl-9-deoxo-8a-aza-8a,6-O- methylene-3-descladinosyl- 11 -O,12-O-carbonyl-8a-homoerythromycin A (32.8 mg, 0.05 mmol) in pyridine (1 mL) was stirred at room temperature as acetic anhydride (0.050 mL, 0.53 mmol) was added.

The resulting solution was capped and stirred overnight. No product was observed by TLC. 4-Dimethylaminopyridine (3.8 mg, 0.031 mmol) and acetic anhydride (0.050 mL, 0.53 mmol) were added and the resulting solution was stirred at 700C for 4 hours. The reaction mixture was then cooled to room temperature and concentrated to a foam. The foam was purified by column chromatography on silica gel (eluted with 1:1 hexane:acetone) to give the title compound (28.1 mg) as a white solid.

1H NMR (CDC13, 500 MHz) 6 2.07 (s, OC(O)CH3), 2.13 (s, OC(O)CH3), 2.28 (s, NMe2), 3.97 and 4.13 (2 d, 8a-CH2-60), 4.19 (d, 1'-H), 4.73 (dd, 2'-H), 4.87 (s, ll-H), 5.03 (dd, 13-H), 5.51 (dd, 3-H).

Step 2: 3 -O-Acetyl-9-deoxo-8a-aza-8a,6-O-methylene-3- descladinosyl-8a-homoerythromvcin A 11 12-carbonate A solution of 2' ,3-bis(O-acetyl)-9-deoxo-8a-aza-8a,6-O- methylene- 3-descladinosyl- 8a-homoerythromycin A 11,12-carbonate (28 mg, 0.039 mmol) in methanol (5 mL) was stirred for 24 h then concentrated under vacuum. The resulting oil was dissolved in benzene and lyophilized to give the title compound (22.8 mg) as a white solid.

1H NMR (CDC13, 500 MHz) 5 2.11 (s, OC(O)CH3), 2.30 (s, NMe2), 3.19 (dd, 2'-H), 3.98 and 4.16 (2 d, 8a-CH2-60), 4.12 (d, 1'-H), 4.87 (s, ll-H), 5.02 (dd, 13-H), 5.59 (dd, 3-H).

EXAMPLE3 9-Deoxo-8a-aza-8a6-0-methvlene-3-descladinosyl-3 -0- methoxyethoxymethyl- 8a-homoerythromycin A 11 12-carbonate Step 1: 2'-O-Acetyl-9-deoxo-8a-aza-8a,6-O-methylene-3- descladinosyl-3 -O-methoxyethoxymethyl-8a- homoervthromvcin A 11.12-carbonate A solution of 2'-O-acetyl-9-deoxo-8a-aza-8a,6-O- methylene-3 -descladinosyl-8 a-homoerythromycin A 11,12-carbonate (100 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) in dichloromethane (0.5 mL) was stirred under a nitrogen atmosphere as 2-methoxyethoxymethyl chloride (0.087 mL, 0.76 mmol) was added dropwise. After stirring overnight at room temperature, the reaction was still not complete. Additional N,N-diisopropylethylamine (0.135 mL, 0.053 mL, & 0.135 mL) and 2-methoxyethoxymethyl chloride (0.087 mL, 0.035 mL, & 0.086 mL) were added to the reaction in three portions over 8 hours. Dichloromethane (2 mL) was also added during this time to facilitate stirring. After stirring overnight, the

reaction was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate. Filtration and evaporation yielded 0.15 g of crude material. The crude product (dissolved in 1:1 hexane:acetone) was loaded onto a silica gel column (30 g, 2.75 cm dia.) and eluted with 1:1 hexane:acetone, collecting 20 mL fractions. Fractions 19-29 were combined, evaporated, and lyophilized from benzene to give the title compound (27.5 mg) as a white solid.

1H NMR (CDC13, 500 MHz) 6 2.05 (s, OC(O)CH3), 2.29 (s, NMe2), 3.40 (s, OCH2OCH2CH2OCH3), 3.57 and 3.79 (2 dt, OCH20CH2CH2OCH3), 3.91 and 4.12 (2 d, 8a-CH2-60), 4.07 (dd, 3-H), 4.48 (d, 1'-H), 4.75 (dd, 2'-H), 4.82 and 4.89 (2 d, OCH2OCH2CH2OCH3), 4.86 (s, 1 l-H), 5.01 (dd, 13-H).

Step 2: 9-Deoxo- 8a-aza-8a,6-O-methylene-3-descladinosyl-3-O- methoxyethoxymethyl-8a-homoerythromycin A 11,12- carbonate A solution of 2'-O-acetyl-9-Deoxo- 8 a-aza- 8a,6-O- methylene-3-descladinosyl-3-O-methoxyethoxymethyl-8a-homoery thro- mycin A 11,12-carbonate (27 mg, 0.036 mmol) was stirred in methanol overnight at room temperature. The reaction was concentrated and half of the mixture was lyophilized (from benzene) to give the title compound (14.4 mg) as a white solid.

1H NMR (CDC13, 500 MHz) 6 2.28 (s, NMe2), 3.21 (dd, 2'-H), 3.40 (s, OCH2OCH2CH2OCH3), 3.57 and 3.79 (2 dt, OCH2OCH2CH2OCH3), 3.93 and 4.13 (2 d, 8a-CH2-60), 4.18 (dd, 3-H), 4.40 (d, 1'-H), 4.83 and 4.88 (2 d, OCH9OCH2CH20CH3), 4.87 (s, ll-H), 5.01 (dd, 13-H).

EXAMPLE 4 <BR> <BR> 9-Deoxo- 8a-aza- 8a6-O-methylene-3 -descladinosvl-3- 0-methoxymethyl- <BR> <BR> 8a-homoerythromycin A- 11 * 12-carbonate Step 1: 2'-O-Acetyl-9-deoxo-8a-aza-8a,6-O-methylene-3- descladinosyl-3 -O-methoxymethyl- 8a-homoerythromycin A 11.12-carbonate A solution of 2'-O-acetyl-9-deoxo- 8a-aza- 8a,6-O- methylene-3-descladinosyl-8 a-homoerythromycin A 11,12-carbonate (31.5 mg, 0.048 mmol) and N,N-diisopropylethylamine (0.046 mL, 0.264 mmol) in dichloromethane (1 mL) was stirred at room tempera- ture as chloromethyl methyl ether (0.018 mL, 0.24 mmol) was added.

The solution was stirred at room temperature for 20 hours and was approximately 33% complete. Over 2.5 hours, N,N-diisopropylethyl- amine (0.046 mL, 0.046 mL, 0.092 mL, & 0.092 mL) and chloro- methyl methyl ether (0.018 mL, 0.018 mL, 0.036 mL, & 0.036 mL) were added portionwise. The reaction was then partitioned between saturated aqueous potassium carbonate and dichloromethane. The organic layer was dried (anhydrous potassium carbonate), filtered, and concentrated to an oil. TLC analysis indicated an 1:1 mixture

of starting material and product. The mixture was chromatographed on a silica gel column (5g, 1.4 cm dia., 8 mL fractions). Fraction 3 was evaporated to give the title compound (9.0 mg) as a solid.

Step 2: 2'-O-Acetyl-9-deoxo-8a-aza-8a,6-O-methylene-3- descladinosyl-3-O-methoxymethyl-8a-homoerythromycin A 11 12-carbonate A solution of 2'-O-acetyl-9-deoxo- 8a-aza-8a,6-O- <BR> <BR> <BR> methylene-3 -descladinosyl- 3-O-methoxymethyl- 8a-homoerythromycin A 11,12-carbonate (9.0 mg, 0.0126 mmol) in methanol (3 mL) was stirred for 20 hours at room temperature. The reaction was concentrated and the residue was lyophilized from benzene to give the title compound (6.9 mg) as a white solid.

1H NMR (CDC13, 500 MHz) 2.28 (s, NMe2), 3.21 (dd, 2'-H), 3.43 (s, OCH2OCH3), 3.92 and 4.13 (2 d, 8a-CH2-60), 4.41 (d, 1'-H), 4.73 and 4.77 (2 d, OCH2OCH3), 4.87 (s, 11-H), 5.02 (dd, 13-H).

EXAMPLE 5 9-Deoxo-8 a-aza-3 -descladinosyl- 8 a-homoerythromycin A 11 12- carbonate-8a-N.6-O-carbamate NMe2 NMe2 Ot,, AcO, N HO, K Oa K(NA XX NaH HO pyridine H THF/Et2O DMAP X , z OMe THF 0 OMe ," THF/Et20 r O DMAP 0 OH 0 OAc

NMe2 NMe2 H AcO4, AcO',,, N ? AcOC 01 M O phosgene 0,, 0 I-, OMe toluene °> > C OMe AcOH OMe DIPEA 0 DlPEA "'S, 0 OAc 0 0OAc NMe2 NMe2 AcQ, e2 N AcO;y½ 0 ts .O HCI ° 0 OMe H OMe OH ¼"' OAc I NMe2 MeOH 0<°^( a °; 01 >I OH o Step 1: 2',4"-bis(O-Acetyl)-9-deoxo-8a-aza-8a-N,6-O-methylene- 8 a-homoerythromycin A A solution of 9-deoxo-8a-aza-8a,6-O-methylene-8a- 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) was cooled to OOC with stirring. Acetic anhydride (3.9 mL, 41.3 mmol) was added dropwise. After 70 minutes, the cooling bath was removed and the reaction was allowed to stir at room temperature for 17 hours. The reaction was partitioned between ethyl acetate and saturated aqueous potassium carbonate. The organic

layer was washed with brine, dried (anhydrous sodium sulfate), filtered, and evaporated to give the title compound (3.08 g) as a white foam.

1H NMR (CDCl3, 500 MHz) 5 2.05 (s, OC(O)CH3), 2.10 (s, OC(O)CH3), 2.29 (s, NMe2), 3.36 (s, 3"-OCH3), 4.38 (m, 5"-H), 4.49 (d, 3-H), 4.68 (d, 4"-H), 4.75 (dd, 2'-H), 4.90 (d, 1'-H).

Step 2: 2',4"-bis(O-Acetyl)-9-deoxo- 8a-aza-8a,6-O-methylene-8a- homoerythromvcin A 11.12-carbonate A solution of 2',4" -bis(O-acetyl)-9-deoxo-8a-aza-8a,6-O- methylene-8a-homoerythromycin A (1.0 g, 1.2 mmol) in anhydrous tetrahydrofuran (7 mL) was stirred at room temperature as sodium hydride (104 mg of 60% dispersion in mineral oil, 2.6 mmol) was added. 1,1'-Carbonyldiimidazole (0.88 g, 5.4 mmol) was then added.

The resulting mixture was stirred at 700C for 80 minutes. Saturated aqueous sodium bicarbonate was added dropwise. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 5% aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the title compound as a light yellow foam (1.09 g).

1H NMR (CDC13, 500 MHz) 5 2.04 (s, OC(O)CH3), 2.09 (s, OC(O)CH3), 2.28 (s, NMe2), 3.35 (s, 3"-OCH3), 3.88 and 4.05 (2 d, 8a-CH2-60), 4.38 (m, 5"-H), 4.49 (d, 3-H), 4.65 (s, ll-H), 4.96 (dd, 13-H), 5.00 (d, 1'-H).

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

organic layers were washed with brine, dried over anhydrous potassium carbonate, and evaporated to give the title compound (0.86 g) as a light yellow foam.

1H NMR (CDCl3, 500 MHz) 5 2.05 (s, OAc), 2.10 (s, OAc), 2.28 (s, NMe2), 3.31 (s, 3"-OCH3), 4.38 (m, 5"-H), 4.75 (d, 2'-H), 4.89 (dd, 13-H), 5.09 (d, l'-H).

Step 4: 2',4" -bis(O-Acetyl)-9-deoxo- 8a-aza-8a-homoerythromycin A 11*12-carbonate-8a-N-6-O-carbamate A solution of 2',4"-bis(O-acetyl)-9-deoxo-8a-aza-8a- homoerythromycin A 11,12-carbonate (0.86 g, 1.02 mmol) and 4- dimethylaminopyridine (32.4 mg, 0.27 mmol) in dichloromethane (8 mL) was stirred under a nitrogen atmosphere. N,N-Diisopropyl- ethylamine (8.0 mL, 45.9 mmol) was added followed by the dropwise addition of phosgene (20% in toluene, 8.0 mL, 20.3 mmol). After stirring overnight at room temperature, the reaction mixture was partitioned between dichloromethane and saturated aqueous potassium carbonate. The organic layer was washed with water, dried (anhydrous potassium carbonate), filtered, and evaporated to an oil (2.23 g, contained N,N-diisopropylethylamine). The oil was lyophilized from benzene to give the title compound as sticky yellow oil (1.29 g).

Step 5: 2'-O-Acetyl-3-descladinosyl-9-deoxo- 8a-aza-8a- homoerythromycin A 1 1,12-carbonate-8a-N,-6-O- carbamate A solution of 2',4"-bis(O-acetyl)-9-deoxo-8a-aza-8a- homoerythromycin A 11,1 2-carbonate-8a-N,6-O-carbamate( 1.29 g) in 0.86M aqueous hydrochloric acid (350 mL) was stirred overnight at room temperature. TLC analysis indicated that the reaction was complete. The solution was made basic with saturated aqueous potassium carbonate and extracted with ethyl acetate (3 x 300 mL).

The combined organic layers were washed with brine, dried (anhydrous sodium sulfate), filtered, and evaporated to a yellow foam. 1H NMR showed some starting material remained. The foam was redissolved

in 1M aqueous hydrochloric acid (180 mL), stirred overnight at room temperature, and worked up as above to give 0.7 g of crude product.

The resulting solid was dissolved in 2:1 hexane:acetone and load onto a silica gel column (2.75 cm dia., 22 g of silica, 20 mL fractions), eluted with the same solvent system. Fractions 31-67 were combined, evaporated, and lyophilized (from benzene) to give the title compound (330 mg).

Step 6: 3 -descladinosyl-9-deoxo- 8a-aza-8a-homoerythromycin A 11 * 12-carbonate-8a-N,-6-O-carbamate A solution of 2'-O-acetyl-9-deoxo-8a-aza-8a,6-O-carbonyl- 11-0,1 2-O-carbonyl-3-descladinosyl-8a-homoerythromycin A (11.1 mg, 0.017 mmol) was stirred in methanol (3 mL) overnight at room temperature. The solvent was evaporated and the residue was lyophilized (from benzene) to give the title compound (10.0 mg) 1H NMR (CDC13, 500 MHz) 5 2.32 (s, NMe2), 2.72 (dd, 9-H), 3.21 (dd, 2'-H), 4.24 (dd, 9-H), 4.56 (d, 1.-H), 4.90 (s, ll-H), 5.13 (dd, 13-H).

EXAMPLE 6 3-descladinosyl-3-oxo-9-Deoxo-8a-aza-8a-homoerythromycin A 11 12- carbonate-8a-N.-6-O-carbamate

Step 1: 2'-O-Acetyl-3-descladinosyl-3-oxo-9-deoxo-8a-aza-8a- homoerythromycin A 11,1 2-carbonate-8a-N,-6-O- carbamate A solution of Dess-Martin periodinane (200.1 mg, 0.47 mmol) and 2 '-O-acetyl-3 -descladinosyl-9-deoxo-8a-aza- 8a-homo- erythromycin A 1 1,12-carbonate-8a-N,-6-O-carbamate (50.8 mg, .076 mmol) in dichloromethane (3 mL) was stirred at reflux for 90 minutes.

The reaction mixture was partitioned between dichloromethane and saturated aqueous potassium carbonate. The layers were separated and the organic layer was washed with water (10 mL), dried (anhydrous potassium carbonate), filtered, and evaporated. The residual solid was dissolved in 1:1 dichloromethane:ether (20 mL). To this stirring solution was added a solution containing sodium bicarbonate (1.3 g) and sodium thiosulfate (4.6 g) in water (15 mL). After 30 minutes, saturated sodium bicarbonate was added and the layers were separated.

The aqueous layer was extracted with ether (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to give a solid (58.2 mg). The solid (dissolved in 2:1 hexane:acetone) was loaded onto a 2 x 14.5 cm silica gel column and was eluted with 2:1 hexane:acetone, collecting 18 mL fractions.

Fractions 22-42 were combined and evaporated to give the title compound (17.6 mg) as a mixture of enols (2:1).

Step 2: 3-descladinosyl-3-oxo-9-deoxo- 8a-aza- 8a- homoerythromycin A 11,12-carbonate- 8a-N,-6-O- carbamate A solution of 2'-O-acetyl-3-descladinosyl- 3-oxo-9-deoxo- 8 a-aza-8 a-homoerythromycin A 11,12-carbonate-8a-N,-6-O-carbamate in methanol (5 mL) was stirred overnight at room temperature. The solvent was evaporated and the residual solid was lyophilized from benzene to give the title compound (13.3 mg) as a white solid (exists in CDCl3 solution as a 4:1 mixture of enol tautomers).

EXAMPLE7 3-descladinosvl-3-deoxv-9-deoxo-8a-aza- 8a-homoerythromvcin A- 1112-carbonate-8a-N*-6-O-carbamate NMe2 NMe2 N S AcO,,,, N Ac o#. O "'" 0 0 0, .O 0 Bu3SnH ""00 " 0 . AlBN s > benzene ) g 0 OH 2) CS2 0 $SMe O {MI 0 NMe2 N AcO,,,, N HO¼j½0 oc< X MeOH O) 0 0 0 0 0

Step 1: 2'-O-Acetyl-3-descladinosyl-3-O-methylxanthyl-9-deoxo- 8a-aza-8a-homoerythromycin A 11,1 2-carbonate-8a-N,6-O- carbamate A solution containing 2'-O-Acetyl-3-descladinosyl-9-deoxo- 8 a-aza- 8a-homoerythromycin A 1 1,1 2-carbonate- 8 a-N,6-O-carb amate (78.4 mg, 0.12 mmol) and N,N-dimethylformamide (2 mL) was cooled to -20°C and placed under a nitrogen atmosphere. After 15 minutes, the reaction was treated with carbon disulfide (0.011 mL, 0.18 mmol).

After stirring for 2 minutes, iodomethane (0.011 mL, 0.18 mmol) was added. After 15 minutes, the resulting solution was allowed to warm to room temperature and stir for 3.33 hours. The reaction was partitioned between dichloromethane and saturated aqueous potassium carbonate.

The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with water (3x), dried over anhydrous potassium carbonate, filtered, evaporated, and lyophilized (from benzene) to afford the title compound (48.9 mg) as a yellow foam.

Step 2: 2'-O-Acetyl-3-descladinosyl-3-deoxy-9-deoxo-8a-aza-8a- homoerythromycin A 11.12-carbonate-8a-N.6-O-carbamate A solution- of 2'-O-Acetyl-3-descladinosyl-3-O-xanthyl- 9-deoxo- 8a-aza- 8a-homoerythromycin A 11,1 2-carbonate-8a-N,6-O- carbamate (20.4 mg, 0.027 mmol) and 2,2'-azobisisobutyronitrile (1.0 mg, 0.006 mmol) in benzene (1.5 mL) was stirred under nitrogen as tributyltin hydride (0.022 mL, 0.082 mmol) was added. The resulting solution was stirred at 900C for 2 hours. The solution was allowed to cool to room temperature, decanted (rinsing ppt. with benzene), and lyophilized to give the desired product as a waxy solid (58.2 mg).

Step 3: 3-descladinosyl-3 -deoxy-9-deoxo-8a-aza-8a- homoerythromycin A 11 1 2-carbonate-8a-N6-O-carbamate A solution of 2'-O-Acetyl-3-descladinosyl-3-deoxy-9- deoxo- 8a-aza- 8a-homoerythromycin A 11,12-carbonate- 8a-N,6-O- carbamate in methanol (4 mL) was stirred overnight. The solvent was removed under vacuum, and the residue was lyophilized from benzene

to give a solid (52.5 mg). The crude product was purified on a silica gel column (7 g, 0.75 inch diameter), eluted with 1:1 hexane:acetone, collecting 8 mL fractions. Fractions 35-60 were combined, evaporated, and lyophilized from benzene to give the title compound (3 mg) as a light yellow solid.

1H NMR (CDC13, 500 MHz) 6 2.32 (s, NMe2), 2.74 (dd, 9-H), 3.22 (dd, 2'-H), 4.22 (dd, 9-H), 4.31 (d, l'-H), 4.88 (s, ll-H), 5.11 (dd, 13- H).

EXAMPLE8 Synthesis of 3-descladinosyl-3-deoxy-8a-N-6-O-methylene-9-deoxo-8a- aza-8a-homoerYthromycin A 11 12-carbonate NMe2 NMe2 AcO¼$%0 0to 0t t 04 0t 1) NaH .O 0 )0, ,SMe S 0 0 Bu3SnH, AIBN Benzene 700C NMe2 NMe2 HO,, N? N AcO,,, ,,,.. ) OOth0 0 0,.. 0" ..%O ".. ..O CH3OH o# 0 o-/ - 0 0 o O O Step 1: 2'-O-Acetyl-3-descladinosyl-3-O-methylxanthyl-8a-N,-6-O- methylene-9- deoxo-8a-aza- 8a-homoerythromycin A 11,12- carbonate Sodium hydride (166 mg of 60% oil dispersion,

4.14 mmol) was added to a cold (-20"C) solution of 2'-O-Acetyl- 3-descladinosyl-8a-N,-6-O-methylene-9-deoxo-8a-aza-8a- homoerythromycin A 11,12-carbonate (905 mg, 1.38 mmol) in anhydrous DMF (11 mL). The reaction mixture was stirred for 15 minutes at -200C then carbon disulfide (0.124 mL, 2.09 mmol) was added. The mixture was stirred for 15 minutes at -200C then iodomethane (0.129 mL, 2.09 mmol) was added and the bath was allowed to warm up. When the bath warmed to -100C, after about 40 minutes, the flask was removed and stirred at room temperature. The mixture was stirred at room temperature for 2 hours by which time the reaction was completed, as determined by TLC. The reaction mixture was poured into ethyl acetate. The organic layer was washed 4 times with saturated aqueous NaHCO3, dried over K2CO3, and filtered.

Removal of solvent under reduced pressure afforded 1.05 g of crude product, estimated purity 85% Step 2: 2'-O-Acetyl-3-descladinosyl-3 -deoxy- 8 a-N,-6-O-methylene- 9-deoxo-8a-aza-8a-homoervthromvcin A 11 12-carbonate The product of step 1 and 23 mg of AIBN (0.14 eq) were dissolved in 20 mL benzene and stirred at 900C. To this, 1.10 mL of Bu3SnH was added and the reaction was heated at reflux for 4 hours.

The reaction was cooled to room temperature and solvent was removed under reduced pressure. The crude material was purified by silica chromatography eluting with 2:1 hexane:acetone. The fractions containing the desired material were combined and solvent removed under reduced pressure to yield 536 mg (0.837) of the title compound (61% yield over 2 steps).

Step 3: 3 -descladinosyl-3 -deoxy-8a-N,-6-O-methylene-9-deoxo-8a- aza-8a-homoerythromycin A 1112-carbonate A solution of 2'-O-Acetyl-3-descladinosyl-3-deoxy-8a- N,-6-O-methylene-9-deoxo-8 a-aza- 8a-homoerythromycin A 11,12- carbonate (537 mg) in methanol (30 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure to afford 503 mg of crude product which was purified by

silica chromatography eluted with 1:1 hexane: acetone to afford the title compound.

1H NMR (CDC13, 500mHz) 55.02 (dd, H-13), 4.87 (s, H-il), 4.23 (d, H-1'), 4.15 (d, H-CH2), 3.92 (d, H-CH2), 3.49 (m, H-5'), 3.38 (d, H-5), 3.20 (dd, H-2'), 2.68 (m, H-8), 2.68 (m, H-2), 2.5 (m, H-3'), 2.41 (dd, H-9), 2.35 (m, H-3), 2.3 (s, NMe2), 2.08 (m, H-4), 2.08 (m, H-9), 1.82 (m, H-14), 1.67 (m, H-4'), 1.61 (m, H-10), 1.60 (m, H-14), 1.49 (m, H- 7), 1.32 (m, H-7), 1.22 (s, H-6'), 1.21 (s, H-2Me), 1.13 (m, H-3), 1.11 (d, H-4Me), 1.05 (d, H-8Me), 0.92 (m, H-15), 0.90 (m, H-lOMe) EXAMPLE 9 <BR> <BR> 3-descladinosyl-3-O-methylxanthyl-8a-N-6-O-methylene-9-deoxo -8a- aza-8a-homoervthromvcin A 11.12-carbonate Step 1: 3 -descladinosyl-3-O-methylxanthyl-8a-N,-6-O-methylene- 9-deoxo-8a-aza-8a-homoerythromvcin A 11.12-carbonate A solution of 2'-O-Acetyl-3-O-methylxanthyl-3-deoxy-8a-N,-6-O- methylene-9-deoxo-8 a-aza-8 a-homoerythromycin A 11,12-carbonate (11 mg) in methanol (4 mL) was stirred at room temperature overnight.

The solvent was removed under reduced pressure and the residue was lyophilized from benzene to afford 8.2 mg of the title compound as a white solid.

EXAMPLE 10 Synthesis of 3-descladinosyl-3-deoxy-9-deoxo-8a-aza-8a- homoerythromycin A 11.12-carbonate

Step 1: 2'-O-Acetyl-3-descladinosyl-3-deoxy-9-deoxo-8a-aza-8a- homoervthromvcin A 11.12-carbonate A solution of 2'-O-Acetyl-3-descladinosyl-3-deoxy-8a- N,-6-O-methylene-9-deoxo- 8a-aza- 8a-homoerythromycin A 11,12- carbonate (20.0 mg, 0.031 mmol) in 1 ml 0.25 M HC1 was stirred at room temperature for 3 hours. The mixture was added to CHC13, neutralized with sat. aq. K2CO3 and extracted with CHCl3. The combined organic layers were washed with sat. aq. K2CO3, dried over anhydrous K2CO3, filtered, and evaporated to afford 9.6 mg of the title compound.

Step 2: 3 -descladinosyl-3 -deoxy-9-deoxo-8a-aza-8a- homoerythromycin A 11.12-carbonate A solution of 2'-O-Acetyl-3-descladinosyl-3-deoxy-9- deoxo-8a-aza-8a-homoerythromycin A 11,12-carbonate (9.4 mg) in methanol (2 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product

was purified by chromatography on a silica gel column eluted with 1:1 (90:10:1 CH2Cl2:CH3OH:methanolic NH3):CH2Cl2 to yield 2.5 mg of the title compound as a white solid.

1H NMR (CDC13, 500 mHz) 3 5.20 (s, H-ll), 4.95 (dd, H-13), 4.30 (d, H-1'), 3.62 (m, H-5'), 3.38 (d, H-5), 3.30 (dd, H-2'), 2.80 (dd, H-9), 2.77 (m, H-8), 2.65 (m, H-2), 2.52 (m, H-3'), 2.31 (m, H-9), 2.30 (s, NMe2), 1.99 (m, H-4), 1.85 (m, H-3), 1.75 (m, H-3), 1.70 (m, H-4'), 1.65 (m, H-7), 1.63 (m, H-14), 1.61 (m, H-10), 1.53 (m, H-7), 1.52 (m, H-14), 1.28 (m, H-4') 1.27 (s, H-6'), 1.24 (s, H-2Me), 1.21 (d, H-8Me), 1.02 (d, H-4Me), 0.97 (m, H-10Me), 0.96 (m, H-15) EXAMPLE 11 Svnthesis of 3-descladinosyl-3-deoxy-9-deoxo-8a-aza-8a-methyl-8a- homoerythromycin A 11 12-carbonate Step 1: 2'-O-Acetyl-3-descladinosyl-3-deoxy-9-deoxo-8a-aza-8a- methyl-8a-homoerythromycin A 11 12-carbonate

Formaldehyde (0.0080 mL, 0.109 mmol) and formic acid (0.0090 mL, 0.212 mmol) were added to a solution of 2'-O-Acetyl-3- descladinosyl-3 -deoxy-9-deoxo-8a-aza-8 a-homoerythromycin A 11,12- carbonate (64 mg, 0.101 mmol) in chloroform (1 mL). The reaction mixture was stirred at 600C for 2 days then diluted with dichloro- methane and water. The pH was adjusted to 4-5 with glacial acetic acid. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed were dried over anhydrous K2CO3, filtered, and evaporated to afford the title compound (62 mg).

Step 2: 3 -descladinosyl-3 -deoxy-9-deoxo-8 a-aza-8a-methyl- 8a- homoerythromvcin A 11.12-carbonate A solution of 2'-O-Acetyl-3-descladinosyl-3-deoxy-9- deoxo-8 a-aza- 8a-methyl- 8a-homoerythromycin A 11,12-carbonate (62 mg, 0.096 mmol) in methanol (5 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by chromatography on a silica gel column eluted with 1:1 hexane:acetone to yield 21.4 mg of the title compound as a white solid.

H NMR (CDC13, 500 mHz) 5 5.31(s, H-ll) ,4.95 (dd, H-13), 4.42 (d, H- 1'), 3.57 (m, H-5'), 3.38 (d, H-5), 3.30 (dd, H-2'), 2.90 (m, H-8), 2.66 (m, H-2), 2.52 (m, H-3'), 2.49 (dd, H-9), 2.30 (s, NMe2), 2.39 (m, H- 9), 2.09 (m, H-4) , 1.96 (m, H-14), 1.71 (m, H-3), 1.70 (m, H-4'), 1.69 (m, H-10), 1.65 (m, H-7), 1.61 (m, H-3), 1.55 (m, H-14), 1.30 (m, H- 4') 1.29 (s, H-6'), 1.24 (s, H-2Me), 1.08 (d, H-8Me), 1.01 (d, H-4Me), 0.96 (m, H-15), 0.95 (m, 11-lOMe).

EXAMPLE 12 3-descladinosyl-3-oxo-9-deoxo- 8a-aza- 8a-N .6-O-methylene-8a- homoervthromvcin A 11 12-carbonate

Step 1: 2' -O-Acetyl-8a-N,6-O-methylene-9-deoxo-8a-aza-8a- homoervthromycin A To a solution of 2.98 g of 9-deoxo-8a-aza-8a- homoerythromycin A in i0 mL of chloroform was added 0.750 mL of 37% aq. formaldehyde. The mixture was refluxed for 1.5 hours, after which time the reaction was diluted with 150 mL chloroform and extracted with 50 mL of sat. aq. potassium carbonate. The organic layer was separated, dried over anhydrous potassium carbonate, and the solvent was removed under reduced pressure. The crude residue was dissolved in 20 mL of 1:1 ethyl acetate:methylene chloride, 0.800 mL of acetic anhydride was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to afford the title compound as a hard foam (3.24 g).

Step 2: 2' -O-Acetyl-8a-N,6-O--methylene-9-deoxo-8a-aza-8a- homoerythromycin A-4"-imidazoylcarbamate- 11,12 carbonate To a solution of 0.103 g (0.127 mmol) of 2'-O-Acetyl-8a- N,6-O--methylene-9-deoxo-8a-aza-8a-homoerythromycin A in 1.0 mL of tetrahydrofuran was added 0.103 g of carbonyldiimidazole (5 eq.), then 12.7 mg of sodium hydride (60% oil dispersion). The mixture was refluxed for 25 minutes, after which time the reaction was diluted with 50 mL ethyl acetate and washed three times with 10 mL of sat. aq.

sodium bicarbonate. The organic layer was separated, dried over anhydrous potassium carbonate, and the solvent was removed under reduced pressureto afford the title compound (103 mg).

1H NMR (CDC13, 500 MHz) 6 5.08 (d, H-1"), 4.99 (d, H-13), 4.80 (d, H-4"), 4.75 (m, H-2'), 4.68 (br s, H-ll), 4.60 (m, H-3), 4.59 (d, H-1'), 4.52 (m, H-5"), 4.08 (d, 6,8a-CH2), 3.89 (d, 6,8a-CH2), 3.55 (m, H- 5'), 3.51 (d, H-5), 2.79 (m, H-2), 2.70 (m, H-3'), 2.62 (m, H-8), 2.42 (d, H-2"), 2.38 (dd, H-9), 2.30 (s, NMe2), 2.13 (m, H-4), 2.07 (s, CH3CO2), 1.99 (dd, H-9), 1.85 (m, H-14), 1.75 (m, H-4'), 1.71 (m, H- 7), 1.71 (dd, H-2"), 1.60 (m, H-10), 1.60 (m, H-14), 1.31 (m, H-4'),

1.31 (m, H-4'), 1.26 (d, 2-Me), 1.10 (d, H-6'), 1.05 (d, 8-Me), 1.00 (d, 4-Me), 0.96 (t, H-15), 0.89 (d, 10-Me).

Step 3: 2' -O-Acetyl-3-descladinosyl-9-deoxo-8a-aza-8a- homoerythromvcin A-11*12 carbonate A solution of 0.110 g (0.127 mmol) of 2'-O-acetyl-8a-N,6- O-methylene-9-deoxo- 8a-aza-8 a-homoerythromycin A-4"-imidazoyl- carbamate-11,12 carbonate in 5.0 mL of 0.25 N aq. HC1 was allowed to stir at room temperature for 12 hours, after which time the reaction was diluted with 50 mL ethyl acetate and washed three times with 30 mL of sat. aq. sodium bicarbonate. The organic layer was separated, dried over anhydrous potassium carbonate, and the solvent was removed under reduced pressure to afford the title compound (78 mg).

1H NMR (CDC13, 500 MHz) 5 4.92 (d, H-13), 4.90 (br s, H-ll), 4.80 (m, H-2'), 4.61 (d, H-1'), 4.08 (br m, H-3), 3.70 (d, H-5), 3.60 (m, H- 5'), 2.86 (m, H-8), 2.80 (dd, H-9), 2.73 (m, H-3'), 2.72 (m, H-2), 2.34 (dd, H-9), 2.29 (s, NMe2), 2.10 (s, CH3CO2), 2.06 (m, H-4), 1.78 (m, H-14), 1.78 (m, H-4'), 1.70 (m, H-7), 1.62 (m, H-10), 1.44 (m, H-7), 1.38 (m, H-4'), 1.32 (d, 2-Me), 1.28 (d, H-6'), 1.18 (d, 8-Me), 0.99 (t, H-15), 0.99 (d, 10-Me), 0.95 (d, 4-Me).

Step 4: 2' -O-Acetyl-3-descladinosyi-8a-N,6-O-methylene-9-deoxo- 8a-aza-8a-homoerythromycin A-11.12 carbonate To a solution of 0.074 g (0.122 mmol) of 2'-O-Acetyl-3- descladinosyl-9-deoxo-8a-aza-8a-homoerythromycin A- 11,12 carbonate in 2.0 mL of chloroform was added 0.050 mL of 37% aq.

formaldehyde. The mixture was refluxed for 1 hour, after which time the reaction was diluted with 150 mL chloroform and extracted with 50 mL of sat. aq. potassium carbonate. The organic layer was separated, dried over anhydrous potassium carbonate, and the solvent was removed under reduced pressure to afford the title compound (64 mg) 1H NMR (CDC13, 500 MHz) 6 5.02 (d, H-13), 4.88 (br s, H-ll), 4.77 (m, H-2'), 4.52 (d, H-1'), 4.19 (d, 6,8a-CH2), 4.01 (dd, H-3), 3.94 (d,

6,8a-CH2), 3.60 (d, H-5), 3.49 (m, H-5'), 2.72 (m, H-2), 2.70 (m, H-3'), 2.68 (m, H-8), 2.43 (dd, H-9), 2.32 (m, H-4), 2.29 (s, NMe2), 2.22 (dd, H-9), 2.05 (s, CH3CO2), 1*88 (m, H-14), 1.75 (d, 3-OH), 1.73 (m, H- 4'), 1.65 (m, H-14), 1.64 (m, H-10), 1.34 (m, H-4'), 1.32 (d, 2-Me), 1.22 (d, H-6'), 1.08 (d, 8-Me), 0.97 (t, H-15), 0.95 (d, 4-Me), 0.92 (d, 10-Me).

Step 5: 2' -Acetoxy-3-descladinosyl-3-oxo-8a-N,6-O-methylene-9- deoxo-8a-aza-8a-homoerythromycin A- 1112 carbonate To a solution of 0.158 g of 2'-O-Acetyl-3-descladinosyl- 8 a-N,6-O-methylene-9-deoxo- 8a-aza-8a-homoerythromycin A- 11,12 carbonate in 1.6 mL of chloroform was added 158 mg of the Dess- Martin periodinane reagent. The mixture was stirred at room temperature for 35 minutes, after which time the reaction was diluted with 30 mL chloroform and 30 mL of saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was back extracted with 15 mL of methylene chloride. The combined organics were dried over anhydrous potassium carbonate, and the solvent was removed under reduced pressure. The crude material was chromatographed on silica gel eluted with 1:1 hexane:acetone. The fractions containing the desired product were combined and evaporated to afford the title compound (116 mg).

1H NMR (CDC13, 500 MHz) 5 5.01 (d, H-13), 4.76 (m, H-2'), 4.71 (br s, H-ll), 4.44 (d, 11-1'), 4.07 (d, H-5), 4.06 (d, 6,8a-CH2), 3.83 (d, 6,8a-CH2), 3.80 (m, H-2), 3.51 (m, H-5'), 3.15 (m, H-4), 2.69 (m, H- 3'), 2.65 (m, H-8), 2.35 (dd, H-9), 2.28 (s, NMe2), 2.06 (s, CH3CO2), 1.98 (dd, H-9), 1.85 (m, H-14), 1.74 (m, H-4'), 1.66 (m, H-10), 1.65 (m, H-14), 1.50 (d, 2-Me), 1.38 (m, H-7), 1.32 (m, H-4'), 1.28 (m, H- 7), 1.22 (d, H-6'), 1.18 (d, 4-Me), 1.06 (d, 8-Me), 0.96 (t, H-15), 0.90 (d, 10-Me).

Step 6: 3-descladinosyl-3-oxo-8a-N,6-O-methylene-9-deoxo-8a- aza-8a-homoervthromycin A-1 12 carbonate A solution of 0.035 g of 2'-O-acetyl-3-descladinosyl-3-oxo- 8a-N,6-O-methylene-9-deoxo-8a-aza-8a-homoerythromycin A- 11,12 carbonate in 2.0 mL of methanol was stirred at room temperature for 5.5 hours, after which time the solvent was removed under reduced pressure. The crude material was chromatographed on silica gel eluting with 1:4 hexane:acetone. The fractions containing the desired product were combined and evaporated to afford the title compound (8 mg).

1H NMR (CDC13, 500 MHz) # 5.02 (d, H-13), 4.69 (br s,H-ll), 4.38 (d, H-1'), 4.10 (d, H-5), 4.06 (d, 6,8a-CH2), 3.85 (d, 6,8a-CH2), 3.82 (m, H-2), 3.53 (m, H-5'), 3.21 (m, H-4), 3.19 (m, H-2'), 2.66 (m, H-8), 2.48 (m, H-3'), 2.32 (dd, H-9), 2.28 (s, NMe2), 1.98 (dd, H-9), 1.85 (m, H-14), 1.68 (m, H-4'), 1.68 (m, H-10), 1.64 (m, H-14), 1.50 (d, 2-Me), 1.48 (m, H-7), 1.33 (m, 4-Me), 1.22 (m, H-4'), 1.22 (d, 6'), 1.06 (d, 8- Me), 0.96 (t, H-15), 0.90 (d, 10-Me).

EXAMPLE 13 3-descladinosvl-3 -deoxv-9-deoxo-8a-aza- 8a-N,6-0-( 1 -oxoethvlene!-8a- homoervthromvcin A

Step 1: 2'-O-acetyl-3 -descladinosyl-3-deoxy-9-deoxo-8a-aza-8a-N- bromoacetyl-8a-homoervthromycin A- 11.12-carbonate To 50 mg (0.080 mmol) of 2'-O-acetyl-3-descladinosyl-3- deoxy-9-deoxo-8a-aza-8a-homoerythromycin A- 11,12-carbonate in 1.5 mL of freshly distilled THF (under N2 atmosphere) was added 0.022 mL of triethylamine (0.160 mmol). After stirring the reaction mixture for 2 minutes, 0.028 mL of bromoacetyl bromide was added to the reaction. After stirring for 1 hour at room temperature, the reaction mixture had solidified and the reaction was judged complete by TLC.

The reaction mixture was extracted with ethyl acetate. The organic layer was washed three times with saturated aqueous NaHCO3, dried over anhydrous K2CO3, filtered, and solvent removed under reduced pressure. The crude product was used in the next step without furthur purification.

Step 2: 3-descladinosyl-3-deoxy-9-deoxo-8a-aza-8a-N,6-O-(l- oxoethylene)- 8a-homoerythromycin A The crude 2'-O-acetyl-3-descladinosyl-3-deoxy-9-deoxo- 8a-aza-8a-N-bromoacetyl-8a-homoerythromycin A- 11,12-carbonate produced in the previous step was dissolved in 2.5 mL of anhydrous DMF then 26 mg of NaH was added. The reaction mixture was stirred at room temperature for 2.5 hours under N2 atmosphere. Thin layer chromatography indicated formation of a lower Rf product. The reaction mixture was extracted into ethyl acetate. The organic layer was washed 1 time with saturated aqueous NaHCO3 and the aqueous wash was back extracted once with EtOAc. The combined organic layers were washed 2 times with NaHCO3, dried over K2CO3, filtered, and solvent removed under reduced pressure. The crude product was purified by silica chromatography eluted with 1:1 hexane:acetone. The fractions containing the desired material were combined and solvent removed under reduced pressure to yield 3 mg of the title compound.

H NMR (CDC13, 500 mHz) d 5.31(dd, H-13) , 5.01(s, H-ll OH), 4.45(d, H-CH2),4.23 (d, 11-1'), 4.12(m, H-8), 4.06 (m, H-9), 4.02 (d, H-CH2), 3.50 (m, 11-5'), 3.46(d, H-5), 3.26(s, H-11), 3.21(dd, H-2'), 2.73(dd, H-9), 2.68(m, H-2), 2.53(m, H-3'), 2.30(s, NMe2), 1.94(m, H- 14), 1.92(m, H-3), 1.84 (m, H-4), 1.70 (m, H-4'), 1.66 (m, H-10), 1.65(m, H-7), 1.51 (m, H-7), 1.48 (m, H-14), 1.38 (d, H-8Me), 1.25(s, H-6'), 1.24(m. H-4'), 1.21(m, H-3), 1.12(d, H-2Me) 1.11 (d, H-4Me), 1.00(d, 11-lOMe), 0.84 (t, H-15)